Diazepinone derivatives

ABSTRACT

The invention relates to compound of the formula I 
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein the substituents are as defined in the specification; to its preparation, to its use as medicament and to medicaments comprising it.

The invention relates to diazepinone derivatives, to their preparation,to their use as medicaments and to medicaments comprising them.

Some mGluR5 antagonists are described e.g. in WO2003047581.

U.S. Pat. No. 3,853,851 describes 5-(oxo, thio orimino)-7,8-dihydro[1,4]diazepino[7.1a]isoquinolines and their use asneuroleptic agents.

mGluR5 antagonists are considered to be useful in the treatment of awide range of disorders, in particular fragile X syndrome (FXS), L-dopainduced dyskinesias in Parkinsons Disease (PD-LID) and Gastro-EsophagealReflux Disease (GERD).

There is a need to provide new mGluR5 antagonists that are good drugcandidates. In particular, preferred compounds should bind potently tomGluR5 whilst showing little affinity for other mGluRs. They shouldexhibit a low binding to plasma proteins. They should be well absorbedfrom the gastrointestinal tract, be sufficiently metabolically stableand possess favorable pharmacokinetic properties. They should benon-toxic and demonstrate few side-effects. Furthermore, the ideal drugcandidate will be able to exist in a physical form that is stable,non-hygroscopic and easily formulated.

The compounds of the invention are mGluR5 antagonists and are thereforepotentially useful in the treatment of a wide range of disorders,particularly FXS, PD-LID and GERD.

In a first aspect, the invention relates to a compound of the formula I

or a salt thereof, whereinA is a fused five- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur;R₁ is halogen; cyano; nitro; hydroxy; amino; —C(O)H; —C(O)NH₂; —X₁—R₅;or —X₂—B₂;X₁ is selected from bond; carbonyl; oxygen; sulfur; —S(O)—; —S(O)₂—;amino, which may be substituted by C₁₋₄alkyl; —NH—C(O)—; —C(O)—NH—;—C(O)—O—; —O—C(O)—; —NH—S(O)₂—; —S(O)₂—NH—; and —NHC(O)NH—;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆carboxyalkyl;C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆-alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl;X₂ is bond or C₁₋₃alkylene, wherein one carbon atom of the C₁₋₃alkylenemay be replaced by a group selected from carbonyl; oxygen; sulfur;—S(O)—; —S(O)₂—; amino, which may be substituted by C₁₋₄alkyl;—NH—C(O)—; —C(O)—NH—; —C(O)—O—; —O—C(O)—; —NH—S(O)₂—; —S(O)₂—NH—; and—NHC(O)NH—;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at the same ring atomtogether are oxo;m is 0, 1, 2, 3 or 4;each R₂ independently is halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;n is 0, 1, 2, 3 or 4;each R₃ independently is halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄-aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;R₄ is hydrogen, halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;B₁ is a five- to six-membered aromatic ring system, which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₇;each R₇ independently ishalogen, cyano, hydroxy, amino,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl;C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl; C₂₋₄halogenalkinyl;C₁₋₄alkoxy; C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy;C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino;C₁₋₄alkoxycarbonyl;or a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₈;each R₈ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at thesame ring atom together are oxo;or two R₇ at adjacent ring atoms atoms form together with said ringatoms a fused five- to seven-membered monocyclic unsaturatednon-aromatic ring system which may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, wherein the ring system mayin turn be substituted once or more than once by R₉;each R₉ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₉ at thesame ring atom together are oxo.

In another aspect, the invention relates to a compound of the formulaI-1

or a salt thereof, whereinA is a fused five- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur;R₁ is halogen; cyano; nitro; hydroxy; amino; —C(O)H; —C(O)NH₂; —X₁—R₅;or —X₂—B₂;X₁ is selected from bond; carbonyl; oxygen; sulfur; —S(O)—; —S(O)₂—;amino, which may be substituted by C₁₋₄alkyl; —NH—C(O)—; —C(O)—NH—;—C(O)—O—; —O—C(O)—; —NH—S(O)₂—; —S(O)₂—NH—; and —NHC(O)NH—;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆carboxyalkyl;C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄-alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl;X₂ is bond or C₁₋₃alkylene, wherein one carbon atom of the C₁₋₃alkylenemay be replaced by a group selected from carbonyl; oxygen; sulfur;—S(O)—; —S(O)₂—; amino, which may be substituted by C₁₋₄alkyl;—NH—C(O)—; —C(O)—NH—; —C(O)—O—; —O—C(O)—; —NH—S(O)₂—; —S(O)₂—NH—; and—NHC(O)NH—;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0, 1, 2, 3 or 4;each R₂ independently is halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;n is 0, 1, 2, 3 or 4;each R₃ independently is halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;R₄ is hydrogen, halogen, cyano, hydroxy, amino, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen;B₁ is a five- to six-membered aromatic ring system, which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₇;each R₇ independently ishalogen, cyano, hydroxy, amino,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl;C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl; C₂₋₄halogenalkinyl;C₁₋₄alkoxy; C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy;C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino;C₁₋₄alkoxycarbonyl;or a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₈;each R₈ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at thesame ring atom together are oxo;or two R₇ at adjacent ring atoms atoms form together with said ringatoms a fused five- to seven-membered monocyclic unsaturatednon-aromatic ring system which may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, wherein the ring system mayin turn be substituted once or more than once by R₉;each R₉ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₉ at thesame ring atom together are oxo.

Unless specified otherwise, the term “compounds of the invention” refersto compounds of formula (I) and subformulae thereof; salts of thecompounds; hydrates or solvates of the compounds and/or salts; as wellas all stereoisomers (including diastereoisomers), tautomers andisotopically labeled compounds (including deuterium substitutions); aswell as inherently formed moieties (e.g. polymorphs, solvates and/orhydrates).

Unless indicated otherwise, the expressions used in this invention havethe following meaning:

“Alkyl” represents a straight-chain or branched-chain alkyl group and,for example, may be methyl, ethyl, n- or iso-propyl, n-, iso-, sec- ortert-butyl; C₁₋₄alkyl typically represents a straight-chain orbranched-chain C₁₋₃alkyl, e.g. methyl, ethyl, n-propyl or iso-propyl.

Each alkyl part of “alkoxy”, “halogenalkyl” and so on shall have thesame meaning as described in the above-mentioned definition of “alkyl”,especially regarding linearity and size.

“C₃₋₆cycloalkyl” represents a saturated alicyclic moiety having fromthree to six carbon atoms. This term refers to groups such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Halogen is generally fluorine, chlorine, bromine or iodine; e.g.fluorine, chlorine or bromine. Halogenalkyl groups typically have achain length of 1 to 4 carbon atoms and are, for example, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl,2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or2,2,3,4,4,4-hexafluorobutyl.

In the context of the invention, the definition of A as a “fused five-to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms” encompasses phenyl, five- to six-membered monocyclicheterocyclic aromatic ring systems, five- to seven-membered monocyclicnon-aromatic hydrocarbon/heterocyclic ring systems. In the context ofthe invention, R₁ is bound to a carbon atoms adjacent to a fusion carbonatom, as it is depicted for compounds of formula (I).

In the context of the invention, the definitions of B₂ and R₇ as a“three- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms” encompasses three- to seven-membered monocyclic aromaticor non-aromatic hydrocarbon groups and aromatic or non-aromaticheterocyclic ring systems of the same sizes.

In the context of the invention, the definition of B₁ as a “five- tosix-membered aromatic ring system which may contain from 1 to 4 heteroatoms” encompasses phenyl or a five- to six-membered monocyclicheterocyclic aromatic ring system.

In the context of the invention, the definition of two R₇ as a “fusedfive- to seven-membered monocyclic unsaturated non-aromatic ring systemwhich may contain from 1 to 4 hetero atoms” encompasses a five- toseven-membered monocyclic unsaturated non-aromatic hydrocarbon group ora five- to seven-membered monocyclic heterocyclic unsaturatednon-aromatic ring system. All said groups/ring systems comprise at leastone double-bond, which is shared with the aromatic ring system B₁ theyare fused to.

Examples of heterocyclic ring systems are: pyrrole, pyrroline,pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline,imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane,dihydrofurane, tetrahydrofurane, oxadiazole, dioxolane, thiophene,dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine,isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline,thiazolidine, isothiazole, isothiazoline, isothiazolidine, thiadiazole,thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine,pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane,tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine,pteridine.

Compounds of formula I may exist in optically active form or in form ofmixtures of optical isomers, e.g. in form of racemic mixtures ordiastereomeric mixtures. In particular, asymmetrical carbon atom(s) maybe present in the compounds of formula I and their salts. Unlessotherwise provided herein, all optical isomers and their mixtures,including the racemic mixtures, are embraced by the invention.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the invention andincludes geometric isomers. It is understood that a substituent may beattached at a chiral center of a carbon atom. The term “chiral” refersto molecules which have the property of non-superimposability on theirmirror image partner, while the term “achiral” refers to molecules whichare superimposable on their mirror image partner. Therefore, theinvention includes enantiomers, diastereomers or racemates of thecompound. “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term is used to designate aracemic mixture where appropriate. “Diastereoisomers” are stereoisomersthat have at least two asymmetric atoms, but which are not mirror-imagesof each other. The absolute stereochemistry is specified according tothe Cahn-Ingold-Prelog R—S system. When a compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. The compounds described herein may contain one ormore asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. Unless otherwiseprovided herein, the invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques.

If the compound contains a double bond, the substituent may be E or Zconfiguration.

If the compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration.

Any asymmetric atom (e.g. carbon or the like) of the compound(s) of theinvention can be present in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R,S)-configuration. In certain embodiments,each asymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated bonds may, ifpossible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein, a compound of the invention can be in theform of one of the possible isomers, rotamers, atropisomers, tautomersor mixtures thereof, for example, as substantially pure geometric (cisor trans) isomers, diastereomers, optical isomers (antipodes), racematesor mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the invention into their opticalantipodes, e.g., by fractional crystallization of a salt formed with anoptically active acid, e.g., tartaric acid, dibenzoyl tartaric acid,diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid,malic acid or camphor-10-sulfonic acid. Racemic products can also beresolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Depending on substituent definition, compounds of formula I may occur invarious tautomeric forms. All tautomeric forms of the compounds offormula I are embraced by the invention.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. The compounds of the invention may be capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

When both a basic group and an acid group are present in the samemolecule, the compounds of the invention may also form internal salts,e.g., zwitterionic molecules.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention that contain groups capable of acting asdonors and/or acceptors for hydrogen bonds may be capable of formingco-crystals with suitable co-crystal formers. These co-crystals may beprepared from compounds of formula (I) by known co-crystal formingprocedures. Such procedures include grinding, heating, co-subliming,co-melting, or contacting in solution compounds of formula I with theco-crystal former under crystallization conditions and isolatingco-crystals thereby formed. Suitable co-crystal formers include thosedescribed in WO 2004/078163. Hence the invention further providesco-crystals comprising a compound of formula (I).

The invention also envisages the use of pro-drugs of the compounds ofthe invention that convert in vivo to the compounds of the invention. Apro-drug is an active or inactive compound that is modified chemicallythrough in vivo physiological action, such as hydrolysis, metabolism andthe like, into a compound of the invention following administration ofthe prodrug to a subject. The suitability and techniques involved inmaking and using pro-drugs are well known by those skilled in the art.Prodrugs can be conceptually divided into two non-exclusive categories,bioprecursor prodrugs and carrier prodrugs. See The Practice ofMedicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego,Calif., 2001).

Furthermore, the compounds of the invention, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the inventionmay inherently or by design form solvates with pharmaceuticallyacceptable solvents (including water); therefore, it is intended thatthe invention embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the invention(including pharmaceutically acceptable salts thereof) with one or moresolvent molecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water. The compounds of theinvention, including salts, hydrates and solvates thereof, mayinherently or by design form polymorphs.

Preferred substituents, preferred ranges of numerical values orpreferred ranges of the radicals present in compounds of the formula Iand the corresponding intermediate compounds are defined below. Thedefinition of the substituents applies to the end-products as well as tothe corresponding intermediates. The definitions of the substituents maybe combined at will, e.g. preferred substituents R₁ and particularlypreferred substituents R₂.

The preferred substituents, preferred ranges of numerical values orpreferred ranges of the radicals present in compounds of the formula I,which are described herein below, are also preferred for compounds ofthe formula I-1 or I0-1.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein A is phenyl.

According to the invention, a compound the formula I or I-1, or saltthereof wherein A is phenyl means a compound of formula I wherein thecycle A, with substituents R1 and R2 as defined herein, is a moiety ofthe formula A0 wherein the two carbon atoms marked by asterisk denotethe positions wherein the moiety is bound in formula I.

Thus, in an aspect, the invention relates to a compound of the formulaI0

or a salt thereof, wherein R1, R2, R3, R4, B1, m and n are as definedherein.

Thus, in an aspect, the invention relates to a compound of the formulaI0-1.

or a salt thereof, wherein R1, R2, R3, R4, B1, m and n are as definedherein.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein A is pyridyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein A is A1

wherein A1 is fused via the two carbon atoms marked by asterisk.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein A is A2

wherein A2 is fused via the two carbon atoms marked by asterisk.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein A is A3

wherein A3 is fused via the two carbon atoms marked by asterisk.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₁—R₅; or —X₂—B₂.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond and B₂ is athree- to seven-membered saturated monocyclic ring system which maycontain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, wherein the ring system may in turn be substituted once or morethan once by R₆; each R₆ independently is halogen, hydroxy, cyano,C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆at the same ring atom together are oxo.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond and B₂ isC₃₋₆cycloalkyl which may be substituted once or more than once by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond and B₂ is a five-to six-membered aromatic ring system which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem may in turn be substituted once or more than once by R₆; each R₆independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond and B₂ ispyridyl, which may be substituted once or more than once by R₆; each R₆independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein m is 0, 1 or 2 and each R₂ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy orC₃₋₆cycloalkyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein m is 0.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein n is 0, 1 or 2 and each R₃ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy orC₃₋₆cycloalkyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein n is 0.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₄ is hydrogen, halogen, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein R₄ is hydrogen.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is phenyl, which may be substituted once ormore than once by R₇.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is phenyl, which may be substituted once ormore than once by R₇; and wherein each R₇ independently is halogen,cyano, hydroxy, amino, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl;C₁₋₄aminoalkyl; C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄halogenalkenyl, C₂₋₄alkinyl,C₂₋₄halogenalkinyl, C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy,C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino, C₁₋₄alkoxycarbonyl, or a three- toseven-membered monocyclic ring system which may be aromatic, saturatedor unsaturated non-aromatic and which may contain from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring systemmay in turn be substituted once or more than once by R₈; each R₈independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at the same ring atomtogether are oxo.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is phenyl, which may be substituted once ormore than once by R₇; and wherein each R₇ independently is halogen,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is a five- to six-membered aromatic ringsystem, which contains from 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur, wherein the ring system may in turn be substitutedonce or more than once by R₇.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is a five- to six-membered aromatic ringsystem, which contains from 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur, wherein the ring system may in turn be substitutedonce or more than once by R₇; and wherein each R₇ independently ishalogen, cyano, hydroxy, amino, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl; C₁₋₄alkylamino-C₁₋₄alkyl;di-(C₁₋₄alkyl)amino-C₁₋₄alkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄halogenalkenyl, C₂₋₄alkinyl, C₂₋₄halogenalkinyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy, C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino, C₁₋₄alkoxycarbonyl, or a three- to seven-memberedmonocyclic ring system which may be aromatic, saturated or unsaturatednon-aromatic and which may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₈; each R₈ independently ishalogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₈ at the same ring atom together are oxo.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is a five- to six-membered aromatic ringsystem, which contains from 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur, wherein the ring system may in turn be substitutedonce or more than once by R₇; and wherein each R₇ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is a five-membered aromatic ring system, whichcontains from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur, wherein the ring system may in turn be substituted once or morethan once by R₇.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is a five-membered aromatic ring system, whichcontains from 1 to 2 nitrogen atoms, wherein the ring system may in turnbe substituted once or more than once by R₇.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is imidazol-1-yl, which may be substituted onceor more than once by R₇.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is imidazol-1-yl, which may be substituted onceor more than once by R₇; and wherein each R₇ independently is halogen,cyano, hydroxy, amino, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl;C₁₋₄aminoalkyl; C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄halogenalkenyl, C₂₋₄alkinyl,C₂₋₄halogenalkinyl, C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy,C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino, C₁₋₄alkoxycarbonyl, or a three- toseven-membered monocyclic ring system which may be aromatic, saturatedor unsaturated non-aromatic and which may contain from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring systemmay in turn be substituted once or more than once by R₈; each R₈independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at the same ring atomtogether are oxo.

In one embodiment, the invention provides a compound of formula I or asalt thereof, wherein B₁ is imidazol-1-yl, which may be substituted onceor more than once by R₇; and wherein each R₇ independently is halogen,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy orC₃₋₆cycloalkyl.

In embodiment E1, the invention provides a compound of formula I or asalt thereof, wherein

A is phenyl;R₁ is —X₂—B₂, wherein X₂ is bond;B₂ is C₃₋₆cycloalkyl which may be substituted once or more than once byR₆;or B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy;m is 0, 1 or 2;each R₂ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;n is 0, 1 or 2;each R₃ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;R₄ is hydrogen, halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy;C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;B₁ is a five- to six-membered aromatic ring system, which contains from1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, whereinthe ring system may in turn be substituted once or more than once by R₇;and wherein each R₇ independently is halogen, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

In one embodiment of E1, the invention provides a compound of formula Ior a salt thereof,

wherein R₁ is —X₂—B₂, wherein X₂ is bond;B₂ is C₃₋₆cycloalkyl which may be substituted once or more than once byR₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment of E1, the invention provides a compound of formula Ior a salt thereof, wherein R₁ is —X₂—B₂, wherein X₂ is bond;

B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment of E1, the invention provides a compound of formula Ior a salt thereof, wherein

m is 0, 1 or 2;each R₂ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;n is 0; andR₄ is hydrogen.

In one embodiment of E1, the invention provides a compound of formula Ior a salt thereof, wherein B₁ is imidazol-1-yl, which may be substitutedonce or more than once by R₇; and wherein each R₇ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

In embodiment E1-1, the invention provides a compound of formula I or1-1, as defined herein, wherein

A is phenyl;R₁ is halogen; cyano; —X₁—R₅; or —X₂—B₂;X₁ is selected from bond; carbonyl and oxygen; preferably bond;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;di(C₁₋₄alkyl)amino-C₁₋₆alkyl; aminocarbonyl-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkinyl;X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0 or is 1 and R₂ is halogen or C₁₋₄alkoxy;andn is 0.

In embodiment E1-2, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;

R₁ is —X₂—B₂;

X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0 or is 1 and R₂ is independently halogen or C₁₋₄alkoxy; andn is 0.

In embodiment E1-3, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;R₁ is halogen; cyano; —X₁—R₅; or —X₂—B₂;X₁ is selected from bond; carbonyl and oxygen; preferably bond;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;di(C₁₋₄alkyl)amino-C₁₋₆alkyl; aminocarbonyl-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkinyl;X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0 or is 1 and R₂ is halogen; andn is 0.

In embodiment E1-4, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;

R₁ is —X₂—B₂;

X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0 or is 1 and R₂ is halogen; andn is 0.

In embodiment E2-1, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;R₁ is halogen; cyano; —X₁—R₅; or —X₂—B₂;X₁ is selected from bond; carbonyl and oxygen; preferably bond;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;di(C₁₋₄alkyl)amino-C₁₋₆alkyl; aminocarbonyl-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkinyl;X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 0;andn is 0.

In embodiment E2-2, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;

R₁ is —X₂—B₂;

X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at the same ring atomtogether are oxo;m is 0;andn is 0.

In embodiment E3-1, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;R₁ is halogen; cyano; —X₁—R₅; or —X₂—B₂;X₁ is selected from bond; carbonyl and oxygen; preferably bond;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;di(C₁₋₄alkyl)amino-C₁₋₆alkyl; aminocarbonyl-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkinyl;X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 1;R₂ is halogen or C₁₋₄alkoxy; andn is 0.

In embodiment E3-2, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;

R₁ is —X₂—B₂;

X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 1;R₂ is halogen or C₁₋₄alkoxy; andn is 0.

In embodiment E3-3, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;R₁ is halogen; cyano; —X₁—R₅; or —X₂—B₂;X₁ is selected from bond; carbonyl and oxygen; preferably bond;R₅ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;di(C₁₋₄alkyl)amino-C₁₋₆alkyl; aminocarbonyl-C₁₋₆alkyl; C₂₋₆alkenyl;C₂₋₆alkinyl;X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 1;R₂ is halogen; andn is 0.

In embodiment E3-4, the invention provides a compound of formula I orI-1, as defined herein, wherein

A is phenyl;

R₁ is —X₂—B₂;

X₂ is bond;B₂ is a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₆ at thesame ring atom together are oxo;m is 1;R₂ is halogen; andn is 0.

In one embodiment of E1-1, E1-2, E1-3, E1-4, E2-1, E2-2, E3-1, E3-2,E3-3 and E3-4, the invention provides a compound of formula I or 1-1, ora salt thereof, wherein R₄ is hydrogen.

In one embodiment of E1-1, E1-2, E1-3, E1-4, E2-1, E2-2, E3-1, E3-2,E3-3 and E3-4, the invention provides a compound of formula I or I-1, ora salt thereof, wherein B₁ is a five- to six-membered aromatic ringsystem, which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₇;

each R₇ independently ishalogen, cyano, hydroxy, amino,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl;C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl; C₂₋₄halogenalkinyl;C₁₋₄alkoxy; C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy;C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino;C₁₋₄alkoxycarbonyl;or a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₈;each R₈ independently is halogen, hydroxy, cyano, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at the same ring atomtogether are oxo;or two R₇ at adjacent ring atoms atoms form together with said ringatoms a fused five- to seven-membered monocyclic unsaturatednon-aromatic ring system which may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, wherein the ring system mayin turn be substituted once or more than once by R₉;each R₉ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₉ at thesame ring atom together are oxo.

In one embodiment of E1-1, E1-2, E1-3, E1-4, E2-1, E2-2, E3-1, E3-2,E3-3 and E3-4, the invention provides a compound of formula I or I-1, ora salt thereof, wherein R₄ is hydrogen and B₁ is a five- to six-memberedaromatic ring system, which may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, wherein the ring system mayin turn be substituted once or more than once by R₇;

each R₇ independently ishalogen, cyano, hydroxy, amino,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl;C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl; C₂₋₄halogenalkinyl;C₁₋₄alkoxy; C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy;C₁₋₄alkyl-amino; di-(C₁₋₄alkyl)amino;C₁₋₄alkoxycarbonyl;or a three- to seven-membered monocyclic ring system which may bearomatic, saturated or unsaturated non-aromatic and which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₈;each R₈ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₈ at thesame ring atom together are oxo;or two R₇ at adjacent ring atoms atoms form together with said ringatoms a fused five- to seven-membered monocyclic unsaturatednon-aromatic ring system which may contain from 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, wherein the ring system mayin turn be substituted once or more than once by R₉;each R₉ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; or two R₉ at thesame ring atom together are oxo.

In one embodiment of E1-1, E1-2, E1-3, E1-4, E2-1, E2-2, E3-1, E3-2,E3-3 and E3-4, the invention provides a compound of formula I or I-1, ora salt thereof, wherein B₁ is imidazol-1-yl, piridin-4-yl, pyrazol-4-ylor 1,2,4-triazol-1-yl which may be substituted once or more than once byR₇; and wherein each R₇ independently is halogen, cyano, hydroxyl,di(C₁₋₄alkyl)amino, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄-alkoxy, C₃₋₆cycloalkyl,C₃₋₆hydroxycycloalkyl or isoxazol-5-yl.

In one embodiment of E1-1, E1-2, E1-3, E1-4, E2-1, E2-2, E3-1, E3-2,E3-3 and E3-4, the invention provides a compound of formula I or I-1, ora salt thereof, wherein R₄ is hydrogen and B₁ is imidazol-1-yl,piridin-4-yl, pyrazol-4-yl or 1,2,4-triazol-1-yl which may besubstituted once or more than once by R₇; and wherein each R₇independently is halogen, cyano, hydroxyl, di(C₁₋₄alkyl)amino,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,C₃₋₆cycloalkyl, C₃₋₆hydroxycycloalkyl or isoxazol-5-yl.

In embodiment E2, the invention provides a compound of formula I or asalt thereof, wherein

A is A1, A2 or A3;

R₁ is —X₂—B₂, wherein X₂ is bond;B₂ is C₃₋₆cycloalkyl which may be substituted once or more than once byR₆;or B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy;m is 0, 1 or 2;each R₂ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;n is 0, 1 or 2;each R₃ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;R₄ is hydrogen, halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy;C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;B₁ is a five- to six-membered aromatic ring system, which contains from1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, whereinthe ring system may in turn be substituted once or more than once by R₇;and wherein each R₇ independently is halogen, C₁₋₄alkyl;C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

In one embodiment of E2, the invention provides a compound of formula Ior a salt thereof,

wherein R₁ is —X₂—B₂, wherein X₂ is bond;B₂ is C₃₋₆cycloalkyl which may be substituted once or more than once byR₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment of E2, the invention provides a compound of formula Ior a salt thereof,

wherein R₁ is —X₂—B₂, wherein X₂ is bond;B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆;each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In one embodiment of E2, the invention provides a compound of formula Ior a salt thereof, wherein

m is 0, 1 or 2;each R₂ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl;n is 0; andR₄ is hydrogen.

In one embodiment of E2, the invention provides a compound of formula Ior a salt thereof, wherein B₁ is imidazol-1-yl, which may be substitutedonce or more than once by R₇; and wherein each R₇ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.

Further examples of suitable compounds of the invention are compoundsselected from the following group P:

Group P: Suitable Compounds of the Invention:

-   9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-chloro-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-chloro-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(thiophen-2-yl)-9-(trifluoromethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-chloro-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(5-methylfuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(6-methoxypyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(2-ethylpyridin-4-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(3-(2-methoxyethoxy)phenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   10-chloro-9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   11-chloro-9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-ethoxyphenyl)-9-methoxy-7-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(4-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(5-methoxy-2-methylphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-fluoro-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(2-(dimethylamino)pyridin-4-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(2-methoxypyridin-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(5-methylfuran-2-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(1-methyl-1H-pyrazol-3-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(1-methyl-1H-pyrazol-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(2-hydroxypropan-2-yl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(2-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(furan-2-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(furan-3-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(1-isopropyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(1-methyl-1H-imidazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-ethyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-ethynyl-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   5-oxo-2-(thiophen-2-yl)-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carbonitrile;-   2-(1-methyl-1H-pyrazol-3-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carbonitrile;-   2-(3-methoxyphenyl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(1-isopropyl-1H-pyrazol-4-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-((dimethylamino)methyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-((2-methoxyethoxy)methyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(1-methoxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-acetyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-methoxyphenyl)-9-phenyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(2-methoxypyridin-4-yl)-9-(pyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(furan-3-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(2-methoxypyridin-4-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(6-fluoropyridin-3-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(3-fluoropyridin-4-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(1-methyl-1H-imidazol-4-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(1-methyl-1H-pyrazol-3-yl)-9-(2-methylpyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,-   (R)-2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(6-oxo-1,6-dihydropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9,10-dimethoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-methoxy-2-(2-oxo-1,2-dihydropyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-isopropyl-1H-imidazol-1-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-chloro-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-iodo-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   1-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carbonitrile;-   2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   methyl    1-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carboxylate;-   2-(2,4-dimethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   ethyl    1-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carboxylate;-   2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclobutyl-1H-imidazol-1-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-imidazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(furan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(5-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(pyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(6-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-chloro-1H-imidazol-1-yl)-9-(5-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(6-fluoropyridin-3-yl)-2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-vinyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(4-fluorophenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(oxazol-2-yl)-1H-imidazol-1-yl)-9-propyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-ethyl-2-(4-isopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-propyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclobutyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclobutyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   4-(6-fluoropyridin-3-yl)-11-(4-isopropyl-1H-imidazol-1-yl)-5,6-dihydro-[1,4]diazepino[1,7-h][1,7]naphthyridin-8(9H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2,6-difluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-ethyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-methylisothiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethynyl-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(2-fluoropyridin-3-yl)-2-(4-(oxazol-2-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(3-fluorooxetan-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxyethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxyethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxyethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-acetyl-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-acetyl-2-(4-cyclobutyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(cyclopent-1-en-1-yl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (S)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclobutyl-1H-imidazol-1-yl)-9-propionyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;    or-   9-(tert-butyl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methylthiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(4-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-hydroxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-methoxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclobutyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-12-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-9-cyclopropyl-12-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-11-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(fluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   (R)-9-cyclopropyl-10-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   10-fluoro-9-(6-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-10-fluoro-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-10-fluoro-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   10-fluoro-9-(2-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   10-fluoro-9-(2-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(6-fluoropyridin-3-yl)-2-(4-(1-methoxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(6-fluoropyridin-3-yl)-2-(4-(3-hydroxyoxetan-3-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   (R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   9-cyclopropyl-2-(4-(oxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(isoxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-methoxy-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(pyridin-4-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-((trifluoromethoxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(1-hydroxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(2-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(1-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(cyclopropyl(hydroxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-((trifluoromethoxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   methyl    2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-(5-fluoropyrazin-2-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-cyclopropyl-2-(4-(1-fluorocyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;-   2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;-   9-isopropoxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;    or salts of these compounds.

In a further aspect, the invention also provides a process for theproduction of compounds of the formula Ia and Ib. Said compounds areobtainable according to the following process as described in scheme 1:

Step 1.1:

A compound of formula VI, in which A, R₂, m, R₃, n and R₄ are as definedunder formula I, and X_(A) is halogen, may be obtained by reacting acompound of formula VII, in which A, R₂, m, R₃, n and R₄ are as definedunder formula I, and X_(A) is halogen, with propylphosphonic anhydride,in the presence of a suitable base, e.g. triethylamine, in the presenceof a suitable solvent, e.g. dichloromethane.

Step 1.2:

A compound of formula V, in which A, R₂, m, R₃, n and R₄ are as definedunder formula I, and X_(A) is halogen, may be obtained by oxidizing thecompound of formula VI with an oxidizing agent, e.g. SeO₂, in thepresence of a suitable solvent, e.g. pyridine.

Step 1.3:

A compound of formula III, in which A, R₂, m, R₃, n and R₄ are asdefined under formula I, and X_(A) is halogen, may be obtained bychlorinating the compound of formula V with a chlorinating agent, e.g.POCl₃, in the presence of a suitable solvent, e.g. 1,2-dichloroethane.

Step 1.4:

A compound of formula Ib, in which A, R₂, m, R₃, n and R₄ are as definedunder formula I, X_(A) is halogen, and B₁ is a five-membered aromaticring system which contains 1 to 4 nitrogen atoms, wherein the ringsystem is bound via a nitrogen atom, and wherein the ring system may inturn be substituted once or more than once by R₇, each R₇ independentlyis as defined under formula I, may be obtained by reacting the compoundof formula III with a compound of formula IV, in which B₁ is afive-membered aromatic ring system which contains 1 to 4 nitrogen atoms,wherein the ring system is bound to the hydrogen marked with an asteriskvia a nitrogen atom, and wherein the ring system may be substituted onceor more than once by R₇, each R₇ independently is as defined underformula I, in the presence of a suitable solvent, e.g.1,2-dichloroethane.

Step 1.5:

A compound of formula Ia,

in which A, R₂, m, R₃, n and R₄ are as defined under formula I, R₁ isC₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆-carboxyalkyl;C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆-aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆, each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo; andB₁ is a five-membered aromatic ring system which contains 1 to 4nitrogen atoms, wherein the ring system is bound via a nitrogen atom,and wherein the ring system may in turn be substituted once or more thanonce by R₇, each R₇ independently is as defined under formula I,may be obtained by reacting the compound of formula Ib with a compoundof formula II,in which R₁ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl;C₁₋₆carboxyalkyl; C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkylcarbonyl-C₁₋₆alkyl;C₁₋₄alkoxycarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl;C₁₋₆aminoalkyl; C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo,in the presence of a catalyst, e.g. Pd(PPh)₃, in the presence of asuitable base, e.g. Na₂CO₃, in the presence of a suitable solvent, e.g.1,2-dimethoxyethane.

In a further aspect, the invention also provides a process for theproduction of compounds of the formula Ia. Said compounds are obtainableaccording to the following process as described in scheme 2:

Step 2.1:

A compound of formula IX, in which

A, R₂, m, R₃, n and R₄ are as defined under formula I, andR₁ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆carboxyalkyl;C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo,may be obtained by reacting a compound of formula V, in which A, R₂, m,R₃, n and R₄ are as defined under formula I, and X_(A) is halogen,with a compound of formula II, in which R₁ is C₁₋₆alkyl;C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆carboxyalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo,in the presence of a catalyst, e.g. Pd(PPh)₃, in the presence of asuitable base, e.g. Na₂CO₃, in the presence of a suitable solvent, e.g.1,2-dimethoxyethane.

Step 2.2:

A compound of formula VIII, in which

A, R₂, m, R₃, n and R₄ are as defined under formula I, X_(A) is halogen,and R₁ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆carboxyalkyl;C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo,may be obtained by chlorinating the compound of formula IX with achlorinating agent, e.g. POCl₃, in the presence of a suitable solvent,e.g. 1,2-dichloroethane.

Step 2.3:

A compound of formula Ia, in which

A, R₂, m, R₃, n and R₄ are as defined under formula I, R₁ is C₁₋₆alkyl;C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl; C₁₋₆-carboxyalkyl; C₁₋₆hydroxyalkyl;C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkylcarbonyl-C₁₋₆alkyl; C₁₋₄alkoxycarbonyl-C₁₋₆alkyl;C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl; C₁₋₆aminoalkyl;C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo; andB₁ is a five-membered aromatic ring system which contains 1 to 4nitrogen atoms, wherein the ring system is bound via a nitrogen atom,and wherein the ring system may in turn be substituted once or more thanonce by R₇, each R₇ independently is as defined under formula I,may be obtained by reacting the compound of formula VIII with a compoundof formula IV, in which B₁ is a five-membered aromatic ring system whichcontains 1 to 4 nitrogen atoms,wherein the ring system is bound to the hydrogen marked with an asteriskvia a nitrogen atom, and wherein the ring system may be substituted onceor more than once by R₇, each R₇ independently is as defined underformula I, in the presence of a suitable solvent, e.g.1,2-dichloroethane.

Further compounds of formula I or their precursors may be obtainablefrom compounds of formula Ia and Ib or their precursors (e.g. compoundsof formulae III)—prepared as described according to scheme 1 or scheme2—by reduction, oxidation and/or other functionalization of resultingcompounds and/or by cleavage of any protecting group(s) optionallypresent, and of recovering the so obtainable compound of the formula I.

Compounds of the formula I can also be prepared by further conventionalprocesses, e.g. as described in the Examples, which processes arefurther aspects of the invention.

The reactions can be effected according to conventional methods, forexample as described in the Examples.

The work-up of the reaction mixtures and the purification of thecompounds thus obtainable may be carried out in accordance with knownprocedures.

Acid addition salts may be produced from the free bases in known manner,and vice-versa.

Starting materials, e.g. compounds of the formulae VII, IV and II areknown or may be prepared according to conventional procedures startingfrom known compounds, for example as described in the Examples.

In a further aspect, the invention also provides a novel compound offormula III

or a salt thereof, wherein A, R₂, m, R₃, n and R₄ are as defined underformula I, and X_(A) is halogen.

In a further aspect, the invention also provides a novel compound offormula V

or a salt thereof, wherein A, R₂, m, R₃, n and R₄ are as defined underformula I, and X_(A) is halogen.

In a further aspect, the invention also provides a novel compound offormula VI

or a salt thereof, wherein A, R₂, m, R₃, n and R₄ are as defined underformula I, and X_(A) is halogen.

In a further aspect, the invention also provides a novel compound offormula VIII

or a salt thereof, wherein A, R₂, m, R₃, n and R₄ are as defined underformula I, and R₁ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl;C₁₋₆carboxyalkyl; C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkylcarbonyl-C₁₋₆alkyl;C₁₋₄alkoxycarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl;C₁₋₆aminoalkyl; C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo.

In one embodiment, the invention provides a compound of formula VIII,wherein A, R₂, m, R₃, n and R₄ are as defined under formula I, and R₁ is—X₂—B₂, wherein X₂ is bond; and B₂ is C₃₋₆cycloalkyl which may besubstituted once or more than once by R₆;

or B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur;wherein the ring system is bound via a carbon atom; and wherein the ringsystem may in turn be substituted once or more than once by R₆; each R₆independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In a further aspect, the invention also provides a novel compound offormula IX

or a salt thereof, wherein A, R₂, m, R₃, n and R₄ are as defined underformula I, and R₁ is C₁₋₆alkyl; C₁₋₆halogenalkyl; C₁₋₆cyanoalkyl;C₁₋₆carboxyalkyl; C₁₋₆hydroxyalkyl; C₁₋₄alkoxy-C₁₋₆alkyl;C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₆alkyl; C₁₋₄alkylcarbonyl-C₁₋₆alkyl;C₁₋₄alkoxycarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonyloxy-C₁₋₆alkyl;C₁₋₆aminoalkyl; C₁₋₄alkylamino-C₁₋₆alkyl; di(C₁₋₄alkyl)amino-C₁₋₆alkyl;aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylaminocarbonyl-C₁₋₆alkyl;di(C₁₋₄alkyl)aminocarbonyl-C₁₋₆alkyl; C₁₋₄alkylcarbonylamino-C₁₋₆alkyl;C₁₋₄alkylaminosulfonyl-C₁₋₆alkyl; di(C₁₋₄alkyl)aminosulfonyl-C₁₋₆alkyl;C₂₋₆alkenyl; C₂₋₆halogenalkenyl; C₂₋₆alkinyl; C₂₋₆halogenalkinyl; or athree- to seven-membered monocyclic ring system which may be aromatic,saturated or unsaturated non-aromatic and which may contain from 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ringsystem is bound via a carbon atom, and wherein the ring system may inturn be substituted once or more than once by R₆; each R₆ independentlyis halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo.

In one embodiment, the invention provides a compound of formula IX,wherein A, R₂, m, R₃, n and R₄ are as defined under formula I, and R₁ is—X₂—B₂, wherein X₂ is bond; and B₂ is C₃₋₆cycloalkyl which may besubstituted once or more than once by R₆;

or B₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur;wherein the ring system is bound via a carbon atom; and wherein the ringsystem may in turn be substituted once or more than once by R₆; each R₆independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the invention can be made up in a solidform including capsules, tablets, pills, granules, powders orsuppositories, or in a liquid form including solutions, suspensions oremulsions. The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers etc.

Typically, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Carriers includeabsorbable pharmacologically acceptable solvents to assist passagethrough the skin of the host. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound of the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They are conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The invention further provides anhydrous pharmaceutical compositions anddosage forms comprising the compounds of the invention as activeingredients, since water may facilitate the degradation of certaincompounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are preferably packagedusing materials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the invention as an active ingredient will decompose. Suchagents, which are referred to herein as “stabilizers,” include, but arenot limited to, antioxidants such as ascorbic acid, pH buffers, or saltbuffers, etc.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

The compounds of formula I or pharmaceutical acceptable salts thereofexhibit valuable pharmacological properties and are therefore useful aspharmaceuticals.

Furthermore, compounds of formula I may be useful for research onmGluR5, e.g. as tool compounds.

In particular, compounds of formula I exhibit an antagonistic action athuman metabotropic glutamate receptor 5 (human mGluR5). This can bedetermined in vitro, for example, at recombinant human mGluR5, usingdifferent procedures like, for example, measurement of the inhibition ofthe agonist induced elevation of intracellular Ca²⁺ concentration inaccordance with L. P. Daggett et al., Neuropharm. Vol. 34, pages 871-886(1995), P. J. Flor et al., J. Neurochem. Vol. 67, pages 58-63 (1996) orby determination to what extent the agonist induced elevation of theinositol phosphate turnover is inhibited as described by T. Knoepfel etal., Eur. J. Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett etal., Neuropharm. Vol. 67, pages 58-63 (1996) and references citedtherein. Isolation and expression of human mGluR subtypes are describedin U.S. Pat. No. 5,521,297.

Selected compounds of formula (I) show IC₅₀ values for the inhibition ofthe agonist (e.g. glutamate or quisqualate) induced elevation ofintracellular Ca2+ concentration or the agonist (e.g. glutamate orquisqualate) induced inositol phosphate turnover, measured inrecombinant cells expressing hmGluR5a of about 1 nM to about 10 μM.

Preferred compounds of formula (I) show an inhibition of said inositolphosphate turnover in recombinant cells expressing hmGluR5a of at least1 μM.

Further preferred compounds of formula (I) show an IC₅₀ value of saidinositol phosphate turnover in recombinant cells expressing hmGluR5a ofat least 500 nM.

Further preferred compounds of formula (I) show an IC₅₀ value of saidinositol phosphate turnover in recombinant cells expressing hmGluR5a ofat least 250 nM.

Further preferred compounds of formula (I) show an IC₅₀ value of saidinositol phosphate turnover in recombinant cells expressing hmGluR5a ofat least 100 nM.

The compounds of the invention may be therefore useful in theprevention, treatment or delay of progression of disorders associatedwith irregularities of the glutamatergic signal transmission, of thegastro-intestinal and urinary tract and of nervous system disordersmediated full or in part by mGluR5.

Disorders associated with irregularities of the glutamatergic signaltransmission are for example epileptogenesis including neuronalprotection after status epilepticus, cerebral ischemias, especiallyacute ischemias, ischemic diseases of the eye, muscle spasms such aslocal or general spasticity, skin disorders, obesity disorders and, inparticular, convulsions or pain.

Disorders of the gastro-intestinal tract include Gastro-EsophagealReflux Disease (GERD), Functional Gastro-intestinal Disorders andPost-operative Ileus.

Functional Gastro-intestinal Disorders (FGIDs) are defined as chronic orrecurrent conditions associated with abdominal symptoms without organiccause using conventional diagnostic measures. A cardinal symptom presentin many FGIDs is visceral pain and/or discomfort. FGIDs includefunctional dyspepsia (FD), functional heartburn (a subset of GERD),irritable bowel syndrome (IBS), functional bloating, functionaldiarrhea, chronic constipation, functional disturbancies of the biliarytract as well as other conditions according to Gut 1999; Vol. 45 Suppl.II. A disorder of particular interest is GERD.

Post-operative Ileus is defined as failure of aboral passage ofintestinal contents due to transient impairment of GI motility followingabdominal surgery.

Disorders of the Urinary Tract comprise conditions associated withfunctional disturbancies and/or discomfort/pain of the urinary tract.Examples of disorders of the urinary tract include but are not limitedto incontinence, benign prostatic hyperplasia, prostatitis, detrusorhyperreflexia, outlet obstruction, urinary frequency, nocturia, urinaryurgency, overactive bladder (OAB), pelvic hypersensitivity, urgeincontinence, urethritis, prostatodynia, cystitis, idiopathic bladderhypersensitivity and the like. OAB is a syndrome characterized byurgency, with or without urinary incontinence, and usually withincreased voiding frequency and nocturia.

Nervous system disorders mediated full or in part by mGluR5 are forexample acute, traumatic and chronic degenerative processes of thenervous system, such as Parkinson's disease, Parkinson's dyskinesia(e.g. L-dopa induced dyskinesia), dyskinesias induced by neuroleptics(e.g. tardive dyskenisia), Tic disorders, Tourette Syndrome, RestlessLeg Syndrome, Periodic Limb Movement Syndromes, senile dementia,Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis,multiple sclerosis and fragile X syndrome, substance-related disorders,psychiatric diseases such as schizophrenia, affective and anxietydisorders, attention deficit disorders and cognitive dysfunctionassociated with these and other CNS disorders. Substance-relateddisorders include substance abuse, substance dependence and substancewithdrawal disorders, e.g. nicotine withdrawal. Anxiety disordersincludes panic disorder, social and specific phobias, anxiety, obsessivecompulsive disorder (OCD), post traumatic stress disorder (PTSD) andgeneralized anxiety disorder (GAD). Affective disorders includedepressive (major depression, dysthymia, depressive disorders NOS) andbipolar disorders (bipolar I and II disorders). Cognitive dysfunctionassociated with these and other CNS disorders include deficits andabnormalities in attention and vigilance, executive functions and memory(for instance working memory and episodic memory). Other disorders whichare mediated fully or in part by mGluR5 are pain and itch.

A disorder of particular interest is L-dopa induced dyskinesia inParkinsons Disease.

The compounds of the invention, especially the compounds as defined ingroup P under Embodiment 8, are useful in the treatment, prevention ordelay of progression of dyskinesias in Parkinsons Disease, especiallyL-dopa induced dyskinesia in Parkinsons Disease. Dyskinesia inParkinsons Disease often, although not exclusively, occurs as aside-effect of treatment of Parkinson's Disease with levodopa (L-dopa),a precursor of dopamine. Characteristics of such dyskinesia includemotor impairment, e.g. the appearance of slow and uncoordinatedinvoluntary movements, shaking, stiffness and problems walking. Patientstreated with L-dopa often have reduced symptoms of Parkinson's Diseasebut they experience increasing difficulties to remain standing or evensitting. After prolonged use of L-dopa, a majority of patients developdyskinesia.

Dyskinesia can occur at any time during the cycle of treatment withL-dopa. In one embodiment, the compounds of the invention are for thetreatment of dyskinesia which occurs at the time of peak L-dopa plasmaconcentrations in the patient. In one embodiment, the compounds of theinvention are for the treatment of dyskinesia which occurs when theL-dopa plasma concentrations in a patient rise or fall (diphasicdyskinesia).

Dyskinesia can also develop in Parkinson's disease sufferers who do nottake L-dopa. In one embodiment, the compounds of the invention are forthe treatment of non-L-dopa induced Parkinson's dyskinesia.

Treatment with a compound of the invention, especially with a compoundas defined in group P, may comprise a reduction in the characteristicsassociated with Parkinson's dyskinesia, including for example, althoughnot limited to, a reduction in the scale of involuntary movements, areduction in the number of involuntary movements, an improvement in theability to carry out normal tasks, an improved ability to walk,increased period of time between episodes of dyskinesia.

In the case of prophylactic treatment, the compounds of the invention,especially the compounds as defined in group P may be used to delay orprevent the onset of Parkinson's dyskinesia.

For the above-mentioned indications (the conditions and disorders) theappropriate dosage will vary depending upon, for example, the compoundemployed, the host, the mode of administration and the nature andseverity of the condition being treated. However, in general,satisfactory results in animals are indicated to be obtained at a dailydosage of from about 0.01 to about 100 mg/kg body weight, preferablyfrom about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg. In largermammals, for example humans, an indicated daily dosage is in the rangefrom about 0.1 to about 1000 mg, preferably from about 1 to about 400mg, most preferably from about 10 to about 100 mg of the compound of theinvention conveniently administered, for example, in divided doses up tofour times a day.

For use according to the invention, a compound of the invention,especially a compound as defined in group P, may be administered assingle active agent or in combination with other active agents, in anyusual manner, e.g. orally, for example in the form of tablets orcapsules, or parenterally, for example in the form of injectionsolutions or suspensions. A combination comprising a compound of theinvention and another active agent will be referred to as “combinationof the invention”.

In the case of Parkinson's dyskinesia induced by L-dopa, the compound ofthe invention, especially being a compound as defined in group P, willbe combined with L-dopa and optionally with at least one active agentselected from the group consisting of a dopa decarboxylase inhibitor, acatechol-O-methyl transferase inhibitor, a dopamine agonist, a monoamineoxidase-B inhibitor, an adrenergic drug, a drug for obstructed airwaydisorders, a beta blocking agent, an alpha-adrenoreceptor antagonist, anangiotensin II antagonist, an anticholinergic, an anticholinesterase, anantidepressant, an anti-inflammatory agent, an anti-rheumatic agent, anantimigraine agent, an anxiolytic, a barbiturate, a barbituratederivate, a belladonna alkaloid, a tertiary amine and a benzothiazepinederivative.

Dopa decarboxylase inhibitors are, for example, carbidopa orbenserazide. Catechol-O-methyl transferase inhibitors are, for example,tolcapone or entacapone. Dopamine agonists are, for example,bromocriptine, pergolide, pramipexole, ropinirole, cabergoline,apomorphine or lisuride.

Monoamine oxidase-B inhibitors are, for example, selegiline, rasagiline.

Adrenergics and/or drugs for obstructed airway disorders are, forexample, Budesonide with formoterol fumarate, Combivent, Sertide mite orSalbutamol.

Beta blocking agents are, for example, Acebutolol, Acebutololhydrochloride, Atenolol, Betaxolol, Betaxolol hydrochloride, Bisoprolol,Bisoprolol fumarate, Bisoprolol hemifumarate, Carvedilol, Cosopt,Levobunolol hydrochloride, Metoprolol, Metoprolol succinate, Metoprololtartrate, Propranolol, Propranolol hydrochloride, Sotalol, Sotalolhydrochloride, Tenoretic, Timolol, Timolol maleate or Timpilo.

Alpha-adrenoreceptor antagonists are, for example, Alfuzosin, Alfuzosinhydrochloride, Doxazosin, Doxazosin mesilate, Tamsulosin, Tamsulosinhydrochloride, Terazosin or Terazosin hydrochloride.

Angiotensin II antagonists are, for example, Candesartan cilexetil,Irbesartan, Losartan, Losartan potassium, Olmesartan medoxomil,Telmisartan or Valsartan.

Combinations of Angiotensin II antagonists are, for example, Blopressplus, Co-diovan, Hyzaar or Karvea hct.

Anticholinergics are, for example, Ibratropium bromide or Tiotropiumbromide.

Anticholinesterases are, for example, Donepezil hydrochloride.

Antidepressants are, for example, Amitriptyline, Amitriptylinehydrochloride, Bupropion hydrochloride, Citalopram, Citalopramhydrobromide, Cyclobenzaprine, Cyclobenzaprine hydrochloride,Escitalopram, Escitalopram oxalate, Fluoxetine, Fluvoxamine maleate,Imipramine hydrochloride, Mirtazapine, Paroxetine, Paroxetinehydrochloride, Sertraline, Sertraline hydrochloride, Trazodone,Trazodone hydrochloride, Venlafaxine or Venlafaxine hydrochloride.

Antiepileptics are, for example, Carbamazepine, Clonazepam, Gabapentin,Phenobarbital, Phenyloin, Pregabalin or Topiramate.

Anti-inflammatory and/or anti-rheumatic agents are, for example,Betamethasone, Betamethasone valerate, Cortisone, Cortisone acetate,Desonide, Diclofenac, Diclofenac sodium, Flurbiprofen, Hydrocortisone,Indometacin, Salicylic acid, Triamcinolone acetonide, Aceclofenac,Aflexa, Arthrotec, Carbager-plus, Celecoxib, Glucosamine, Glucosaminesulfate, Glucosamine with chondroitin, Ibuprofen, Ketoprofen, Meloxicam,Naproxen, Naproxen sodium, Nimesulide, Osteo bi-flex or Sulindac.

Antimigraine preparations are, for example, Naratriptan hydrochloride,Rizatriptan or Sumatriptan.

Anxiolytics are, for example, Alprazolam, Bromazepam, Clonazepam,Clorazepate dipotassium, Diazepam, Ethyl loflazepate, Hydroxyzine,Hydroxyzine hydrochloride, Lorazepam, Oxazepam or Tetrazepam.

Barbiturates and/or barbiturate derivates are, for example,Phenobarbital or Phenobarbital.

Belladonna alkaloids and/or tertiary amines are, for example,Hyoscyamine sulfate Benzodiazepine derivatives and related drugs are,for example, Alprazolam, Bromazepam, Clonazepam, Clorazepatedipotassium, Diazepam, Ethyl loflazepate, Lorazepam, Lormetazepam,Oxazepam, Temazepam, Tetrazepam, Triazolam, Eszopiclone, Zolpidem,Zolpidem tartrate or Zopiclone.

Benzothiazepine derivatives are, for example, Diltiazem or Diltriazemhydrochloride.

In one embodiment of the invention a specific combination of theinvention is used. Said combination comprises:

A compound of the invention, especially a compound as defined in groupP; and L-dopa.

In one embodiment of the invention a specific combination of theinvention is used. Said combination comprises:

A compound of the invention, especially a compound as defined in groupP;

L-dopa; and

at least one active agent selected from the group consisting of:carbidopa, benserazide, tolcapone, entacapone, bromocriptine, pergolide,pramipexole, ropinirole, cabergoline, apomorphine, lisuride, selegiline,rasagiline, Budesonide with formoterol fumarate, Combivent, Sertidemite, Salbutamol, Acebutolol, Acebutolol hydrochloride, Atenolol,Betaxolol, Betaxolol hydrochloride, Bisoprolol, Bisoprolol fumarate,Bisoprolol hemifumarate, Carvedilol, Cosopt, Levobunolol hydrochloride,Metoprolol, Metoprolol succinate, Metoprolol tartrate, Propranolol,Propranolol hydrochloride, Sotalol, Sotalol hydrochloride, Tenoretic,Timolol, Timolol maleate, Timpilo, Alfuzosin, Alfuzosin hydrochloride,Doxazosin, Doxazosin mesilate, Tamsulosin, Tamsulosin hydrochloride,Terazosin, Terazosin hydrochloride, Candesartan cilexetil, Irbesartan,Losartan, Losartan potassium, Olmesartan medoxomil, Telmisartan,Valsartan, Blopress plus, Co-diovan, Hyzaar, Karvea hct, Ibratropiumbromide, Tiotropium bromide, Donepezil hydrochloride, Amitriptyline,Amitriptyline hydrochloride, Bupropion hydrochloride, Citalopram,Citalopram hydrobromide, Cyclobenzaprine, Cyclobenzaprine hydrochloride,Escitalopram, Escitalopram oxalate, Fluoxetine, Fluvoxamine maleate,Imipramine hydrochloride, Mirtazapine, Paroxetine, Paroxetinehydrochloride, Sertraline, Sertraline hydrochloride, Trazodone,Trazodone hydrochloride, Venlafaxine, Venlafaxine hydrochloride,Carbamazepine, Clonazepam, Gabapentin, Phenobarbital, Phenyloin,Pregabalin, Topiramate, Betamethasone, Betamethasone valerate,Cortisone, Cortisone acetate, Desonide, Diclofenac, Diclofenac sodium,Flurbiprofen, Hydrocortisone, Indometacin, Salicylic acid, Triamcinoloneacetonide, Aceclofenac, Aflexa, Arthrotec, Carbager-plus, Celecoxib,Glucosamine, Glucosamine sulfate, Glucosamine with chondroitin,Ibuprofen, Ketoprofen, Meloxicam, Naproxen, Naproxen sodium, Nimesulide,Osteo bi-flex or Sulindac. Antimigraine preparations are, for example,Naratriptan hydrochloride, Rizatriptan, Sumatriptan, Alprazolam,Bromazepam, Clonazepam, Clorazepate dipotassium, Diazepam, Ethylloflazepate, Hydroxyzine, Hydroxyzine hydrochloride, Lorazepam,Oxazepam, Tetrazepam, Phenobarbital, Phenobarbital, Hyoscyamine sulfate,Alprazolam, Bromazepam, Clonazepam, Clorazepate dipotassium, Diazepam,Ethyl loflazepate, Lorazepam, Lormetazepam, Oxazepam, Temazepam,Tetrazepam, Triazolam, Eszopiclone, Zolpidem, Zolpidem tartrate,Zopiclone, Diltiazem and Diltriazem hydrochloride.

An example of a combination is a compound as defined in group P, L-dopa,and the dopa decarboxylase inhibitor carbidopa.

Another example of a combination is a compound as defined in group P,L-dopa, and entacapone.

Another example of a combination is a compound as defined in group P,L-dopa, entacapone, and carbidopa; an example of such a combination is acombination of a compound as defined in group P and Stalevo®.

An example of a combination is the first compound as defined in group P,i.e.9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,L-dopa, and the dopa decarboxylase inhibitor carbidopa.

Another example of a combination is the first compound as defined ingroup P, i.e.9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,L-dopa, and entacapone.

Another example of a combination is the first compound as defined ingroup P, i.e.9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,L-dopa, entacapone, and carbidopa; an example of such a combination is acombination of the first compound as defined in group P, i.e.9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,and Stalevo®.

The agents of the present invention may also be useful for treating orpreventing migraine.

The agents of the present invention may also be useful for inflammatorydiseases, such as pain, inflammation and/or oedema consequential totrauma, for example associated with burns, sprains, fractures or thelike, inflammatory airways diseases, such as COPD, asthma, rhinitis,inflammatory bowel disease, cystitis, uveitis, inflammatory skindisorders, such as psoriasis or eczema, rheumatoid arthritis, use as asmooth muscle relaxant, for example for the treatment of spasms of thegastro-intestinal tract or uterus, for example in the therapy of Crohn'sdisease, ulcerative collitis or pancreatitis, or for the treatment ofmuscle spasticity and tremor, for example in multiple sclerosis,teno-synovitis, gout, ocular disorders, for example glaucoma, cough.

The agents of the present invention may also be useful for treatingcognitive impairment and/or attention deficit disorder.

Cognitive dysfunction include deficits and abnormalities in attentionand vigilance, executive functions and memory (for instance workingmemory and episodic memory). Other disorders relating to cognitivedysfunction include sleep related breathing disorders (SRBD), behavioralimpairments, information processing deficits and age-related disorders.

Further examples falling of cognitive impairment and/or attentiondeficit disorders include: Attention-deficit hyperactivity disorder(ADHD), childhood ADHD, adult ADHD, excess daytime somnolence, sleepapnea, shift-worker's sleep-wake cycle disruption, traumatic braininjury, neurodegenerative disorders with associated memory and cognitiveproblems (such as Alzheimer's disease, Lewy body dementia, seniledementia, vascular dementia, Parkinson's disease), chronic fatiguesyndrome, fatigue associated with sleep deprivation or prolongedwakefulness, age-related decline in memory and cognitive function (suchas mild cognitive impairment), cognitive impairment associated with mooddisorders (such as depression) and anxiety, schizophrenia, day timesleepiness associated with narcolepsy.

Furthermore, the agents of the present invention may provide treatmentfor or improve of the cognitive enhancement of a subject. The term“cognitive enhancement” includes, but is not limited to, cognitionenhancement, vigilance, counteracting effects of fatigue, enhancingalertness, attention, memory (working, episodic), learning ability,reaction time, cognitive performance enhancement, excess daytimesomnolence, reversal of information processing deficits, improvement ofdisorganization, i.e. improving organizational skills/level oforganizational ability.

The agents of the present invention may also be useful for treatingpervasive developmental disorders (PDD). PDD is a group of diseasescharacterized by a delay in the development of socialization andcommunications skills. The following diseases are part of the PDD:Autism, Asperger's syndrome, childhood disintegrative disorder, andRett's syndrome, and fragile X. The main symptomatology are:Autistic-like behavior, repetitive behavior (OCD), in some casesirritability, and ADHS. Fragile X Syndrome have two differentgenotype-phenotype: Full mutation (mental retardation, ADHD, autism, andanxiety), partial mutation (tremor-ataxia, parkinsonism, anxiety). Adisorder of particular interest is fragile X syndrome.

The compounds of the invention may be useful for the prevention of theabove-mentioned conditions and disorders.

The compounds of the invention may be useful for the treatment of theabove-mentioned conditions and disorders.

The compounds of the invention may be useful for the delay ofprogression of the above-mentioned conditions and disorders.

Compounds of the invention may be especially useful in the treatment ofan indication selected from: L-dopa induced dyskinesias in ParkinsonsDisease and fragile X syndrome.

Thus, as a further embodiment, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof asa medicament.

As a further embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in therapy.

In a further embodiment, the therapy is selected from a disease which isameliorated by inhibition of mGluR5. In another embodiment, the diseaseis selected from the afore-mentioned list, e.g. L-dopa induceddyskinesias in Parkinsons Disease and fragile X syndrome.

In another embodiment, the invention provides a method of treating adisease which is ameliorated by inhibition of mGluR5 comprisingadministration of a therapeutically acceptable amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In a furtherembodiment, the disease is selected from the afore-mentioned list,suitably L-dopa induced dyskinesias in Parkinsons Disease and fragile Xsyndrome.

The term “a therapeutically effective amount” of a compound of theinvention refers to an amount of the compound of the invention that willelicit the biological or medical response of a subject, for example,reduction or inhibition of an enzyme or a protein activity, orameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the invention that, when administered to a subject, iseffective to (1) at least partially alleviating, inhibiting, preventingand/or ameliorating a condition, or a disorder or a disease (i) mediatedby mGluR5, or (ii) associated with mGluR5 activity, or (iii)characterized by abnormal activity of mGluR5; or (2) reducing orinhibiting the activity of mGluR5; or (3) reducing or inhibiting theexpression of mGluR5. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the invention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reducing or inhibiting the activity of mGluR5; or at leastpartially reducing or inhibiting the expression of mGluR5.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

The pharmaceutical composition or combination of the invention can be inunit dosage of about 1-1000 mg of active ingredient(s) for a subject ofabout 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg orabout 0.5-100 mg, or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of theinvention can be applied in vitro in the form of solutions, e.g.,preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound of the invention can be assessed by in vitro& in vivo methods described herein.

The compound of the invention may be administered either simultaneouslywith, or before or after, at least one other therapeutic agent. Thecompound of the invention may be administered separately, by the same ordifferent route of administration, or together in the samepharmaceutical composition.

The following Examples illustrate the invention, but do not limit it.

EXPERIMENTAL PART General

For reactions run in a microwave reactor, the model Initiator® fromBiotage, heating with high-frequency microwaves of 2.45 GHz, was used.

Analytical UPLC/MS conditions (%=percent by volume): Waters Acquity UPLCsystem, column Acquity HSS-T3 1.8 μm; 2.1×50 mm; T=50° C.; gradient: A,water+0.05% HCOOH+0.05% ammonium acetate; B, acetonitrile+0.4% HCOOH;from NB 98/2 to 2/98 in 1.4 min+0.57 min isocratic; flow rate 1.2mL/min.

1H NMR spectra were acquired on a Bruker spectrometer (360, 400 or 600MHz). Chemical shifts are given in parts per million (ppm) relative tothe residual solvent peak.

Abbreviations:

-   AcOEt ethyl acetate-   AcOH acetic acid-   cHex cyclohexane-   CO carbon monoxide-   DCM dichloromethane-   DMA dimethylacetamide-   DME 1,2-dimethoxyethane-   DMF dimethylformamide-   DMF-DMA N,N-Dimethylformamide dimethyl acetal-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   eq equivalent-   h hour-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   MeOH methanol-   mg milligram-   min minute-   mL milliliter-   MPLC medium pressure chromatography-   MS mass spectrometry-   NMM N-methyl morpholine-   NMP N-methylpyrrolidone-   PEPPSI-iPr    [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)    dichloride-   rt retention time-   RT room temperature-   T3P propylphosphonic anhydride solution-   TBME tert-butylmethylether-   TBTU O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   UPLC ultra pressure liquid chromatography

Preparations 1-27 Preparation 1: 5-iodo-1-methyl-3,4-dihydroisoquinoline

Step 1. N-(2-iodophenethyl)acetamide

A solution of 2-(2-iodophenyl)ethanamine (13.5 g, 54.6 mmol) and Ac₂O(10.3 mL, 109 mmol) in 1,4-dioxane (200 mL) was heated to 100° C. for 45min. The reaction was then allowed to cool to RT and concentrated invacuo. The resulting residue was taken up in DCM and washed with asaturated aq. solution of NaHCO₃—gas formation! The organic phase wasseparated, dried over Na₂SO₄, filtered and concentrated in vacuo to givethe title compound as a yellow oil (16.2 g) which was used as it is inthe next step. UPLC-MS: MS 290.3 (M+H⁺); UPLC rt 0.96 min.

Step 2.7-iodo-10b-methyl-5,6-dihydro-2H-oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione

A solution of N-(2-iodophenethyl)acetamide (16.0 g, 55.3 mmol) in DCM(600 mL) under N2, was treated dropwise with (COCl)₂ (5.33 mL, 60.9mmol). The reaction was stirred at RT for 45 min and then cooled to 0°C. FeCl₃ (10.8 g, 66.4 mmol) was then added and the mixture was allowedto slowly warm to RT and stirred at RT for 18 h. An aq. solution of 2NHCl (50 mL) was added and the mixture was stirred for 2 h. The organicphase was separated, dried over Na₂SO₄, filtered and concentrated invacuo to provide the title compound as a brown solid (20.8 g) that wasused as it is in the next step. UPLC-MS: MS 344.3 (M+H⁺); UPLC rt 1.10min.

Step 3. 5-iodo-1-methyl-3,4-dihydroisoquinoline

A suspension of7-iodo-10b-methyl-5,6-dihydro-2H-oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione(20.7 g; 60.3 mmol) in MeOH/H₂SO₄ (19:1, 750 mL) was heated to refluxfor 5 h. The mixture was cooled to RT and concentrated in vacuo. Theresulting residue was taken up in H2O (200 mL) and extracted with AcOEt.The org. phases was separated and extracted twice with a 1 N aqueous HClsolution. The aqueous phases were combined, cooled with ice and renderedbasic with a concentrated aqueous solution of ammonia. This mixture wasextracted with DCM, and the combined org. layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified byflash chromatography (SiO2, DCM to DCM/MeOH 95:5) to give the titlecompound as a brown solid (8.6 g). UPLC-MS: MS 272.3 (M+H⁺); UPLC rt0.606 min. ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.37 (s, 3H); 2.68-2.78(m, 2H); 3.68 (td, J=7.62, 1.56 Hz, 2H); 7.04 (t, J=7.82 Hz, 1H); 7.46(d, J=7.43 Hz, 1H); 7.84 (d, J=7.82 Hz, 1H).

Following the procedure described above for Preparation 1 andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingbuilding block of the present invention were prepared:

Preparation 2: 5-fluoro-1-methyl-3,4-dihydroisoquinoline

MS 164.0 (M+H⁺). UPLC (2 min) rt 0.616 min.

Preparation 3: 5-chloro-1-methyl-3,4-dihydroisoquinoline

UPLC-MS: MS 180.1 (M+H⁺); UPLC rt 0.25 min.

Preparation 4: 5-bromo-1-methyl-3,4-dihydroisoquinoline

MS 224.0 (M+H⁺). UPLC (2 min) rt 0.743 min.

Preparation 5: 1-methyl-5-(trifluoromethyl)-3,4-dihydroisoquinoline

MS 214.0 (M+H⁺). UPLC (2 min) rt 0.805 min.

Preparation 6: 5-methoxy-1,3-dimethyl-3,4-dihydroisoquinoline

UPLC-MS: MS 190.0 (M+H⁺); UPLC rt 0.58 min.

Preparation 7: 6-chloro-5-methoxy-1-methyl-3,4-dihydroisoquinoline

UPLC-MS: MS 210.0 (M+H⁺); UPLC rt 0.41 min.

Preparation 8: 7-chloro-5-methoxy-1-methyl-3,4-dihydroisoquinoline

UPLC-MS: MS 210.0 (M+H⁺); UPLC rt 0.59 min.

The following examples provide synthetic route to starting materialuseful for the preparation of compounds described in this invention:

Preparation 9: 2-(3-chloro-2-methoxyphenyl)ethanamine

Step 1. 1-(bromomethyl)-3-chloro-2-methoxybenzene

A mixture of 4-chloro-2-methoxy-1-methylbenzene (26.5 g, 169 mmol), NBS(33.1 g, 186 mmol) and benzoyl peroxide (200 mg, 0.826 mmol) in CHCl₃was heated to reflux for 24 h. The reaction was allowed to cool to RTand then concentrated in vacuo. The residue was stirred with petroleumether and the resulting suspension was filtered off and the filtrate wasconcentrated in vacuo to give the title compound (30.9 g) as brown oil,which was used as it is in the next step. UPLC (2 min) rt 1.708 min.

Step 2. 2-(3-chloro-2-methoxyphenyl)acetonitrile

A solution of 1-(bromomethyl)-3-chloro-2-methoxybenzene (30.8 g, 131mmol) in EtOH (150 mL) at RT and under N₂ was treated with an aq.solution of NaCN (12.8 g, 262 mmol in 50 mL H₂O) and the mixture washeated to 100° C. for 3 h. The reaction was then cooled to RT and takenup in Et₂O. The mixture was washed with H₂O and brine, and the aq. phasewas extracted again with Et₂O. The combined org. layers dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (SiO₂, Hexane to Hexane/AcOEt 4:1) toafford the title compound (15.8 g) as brown oil. UPLC (2 min) rt 1.383.

Step 3. 2-(3-chloro-2-methoxyphenyl)ethanamine

A suspension of 2-(3-chloro-2-methoxyphenyl)acetonitrile (15.8 g, 87mmol) and Ra—Ni (87 mmol) in MeOH/NH₃ (96:4, 200 mL) was stirred at RTunder an atmosphere of H₂ for 33 h. The mixture was then filtered andthe filtrate was concentrated in vacuo to give the title compound (15.8g) as a brownish liquid that was used as it is in the next step.UPLC-MS: MS 186.0 (M+H⁺); UPLC rt 0.43 min.

Following the procedure described above for2-(3-chloro-2-methoxyphenyl)ethanamine and substituting the appropriatereagents, starting materials and purification methods known to thoseskilled in the art, the following intermediate was prepared:

Preparation 10: 2-(4-chloro-2-methoxyphenyl)ethanamine

UPLC-MS: MS 186.0 (M+H⁺); UPLC rt 0.62 min.

Preparation 11: 4-(1-methyl-3,4-dihydroisoquinolin-5-yl)morpholine

A flask under Ar was charged with5-iodo-1-methyl-3,4-dihydroisoquinoline (8.0 g, 29.5 mmol), morpholine(3.1 g, 35.4 mmol) and Cs₂CO₃ (13.5 g, 41.3 mmol) and a mixture ofPd(OAc)₂ (0.33 g, 1.48 mmol) and BINAP (0.92 g, 1.48 mmol) in toluene(150 mL) was added. The reaction was stirred at RT for 5 min and thenheated to reflux for 24 h. The reaction was allowed to cool to RT, andthen filtered over celite. The filtrate was concentrated in vacuo andthe crude product was purified by flash chromatography (SiO₂, DCM toDCM/MeOH 9:1) to provide the title compound (3.05 g). UPLC-MS: MS 231.1(M+H⁺); UPLC rt 0.40 min.

Preparation 12: 2-(1-methyl-3,4-dihydroisoquinolin-5-yl)propan-2-ol

Step 1. 1-(1-methyl-3,4-dihydroisoquinolin-5-yl)ethanone

A solution of 5-iodo-1-methyl-3,4-dihydroisoquinoline (2.0 g, 7.38mmol), Pd(OAc)₂ (41 mg, 0.184 mmol) and DPPP (85 mg, 0.207 mmol) in dryDMSO (15 mL) was degassed, and butylvinyl ether (4.80 mL, 36.9 mmol) andEt₃N (1.24 mL, 8.85 mmol) were then added in succession. The reactionwas heated to 100° C. for 18 h, and then allowed to cool to RT. Themixture was diluted with Et₂O and washed with H₂O. The organic phase wasthen dried over Na₂SO₄, filtered and concentrated in vacuo to give abrown oil that was taken up in THF (50 mL) and treated with a 2N aq.solution of HCl (25 mL). The mixture was stirred at RT for 4 h, and thendiluted with AcOEt and washed with H₂O. The aq. phase was thenneutralized and rendered basic by adding Na₂CO₃, and then extracted withAcOEt. The combined org. layers were then dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, DCM to DCM/MeOH 9:1) to provide the title compound(1.06 g) as a brown oil, which was used as it is in the next step.UPLC-MS: MS 188.0 (M+H⁺); UPLC rt 0.45 min.

Step 2. 2-(1-methyl-3,4-dihydroisoquinolin-5-yl)propan-2-ol

A solution of 1-(1-methyl-3,4-dihydroisoquinolin-5-yl)ethanone (800 mg,4.27 mmol) in dry Et₂O (10 mL) under Ar was cooled to −78° C., and thentreated dropwise with a 3M solution of MeMgBr (1.42 mL, 4.27 mmol). Themixture was stirred at −78° C. for another 30 min. It was then allowedto warm to RT and stirred for 18 h at RT. The reaction was then dilutedwith AcOEt and washed with H₂O. The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by flash chromatography(SiO₂, DCM to DCM/MeOH 9:1) afforded2-(1-methyl-3,4-dihydroisoquinolin-5-yl)propan-2-ol (166 mg) as a brownoil. UPLC-MS: MS 204.2 (M+H⁺); UPLC rt 0.47 min.

Preparation 13: 1-methyl-5-(pyridin-4-yl)-3,4-dihydroisoquinoline

A mixture of 5-iodo-1-methyl-3,4-dihydroisoquinoline (3.0 g, 11.1 mmol),pyridin-4-ylboronic acid (2.04 g, 16.6 mmol), Pd(PPh₃)₂Cl₂ (3.88 g, 5.53mmol) and Cs₂CO₃ (10.8 g, 33.2 mmol) in 1,4-dioxane (45 mL) was heatedto reflux for 24 h. The mixture was allowed to cool to RT, and thenfiltered. The filter cake was washed with AcOEt, and the filtrate wasthen concentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, DCM to DCM/MeOH 9:1) to afford the title compound(1.82 g) as a grey solid. UPLC-MS: MS 223.0 (M+H⁺); UPLC rt 0.38 min.

Preparation 14:9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

Step 1. (Z)-ethyl 2-(5-iodo-3,4-dihydroisoquinolin-1(2H)-ylidene)acetate

To a yellow cooled solution of 5-iodo-1-methyl-3,4-dihydroisoquinoline(30.1 g, 111 mmol) in dry THF (900 mL) was added dropwise a solution ofLDA (2M in THF, 111 mL, 222 mmol) at −78° C. The resulting brownsolution was stirred for at −78° C. for 45 min and a solution of diethylcarbonate (14 mL, 116 mmol) in THF (80 mL) was then added dropwise. Themixture was stirred at −78° C. for another 45 min, and then poured ontobrine. The resulting yellow suspension was filtered and the filter cakewas washed with AcOEt. The filtrate was extracted with AcOEt, and thecombined org. phases were dried over Na₂SO₄, filtered and concentratedin vacuo to give the title compound (40.0 g) as a brown oil that wasused as it is in the next step. UPLC-MS: MS 344.1 (M+H⁺); UPLC rt 1.28min.

Step 2. ethyl 2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

A solution of (Z)-ethyl2-(5-iodo-3,4-dihydroisoquinolin-1(2H)-ylidene)acetate (40.0 g, 116mmol) in dry EtOH (430 mL) was treated with AcOH (33 mL) and NaBH₃CN(9.63 g, 146 mmol) portionwise at RT under Ar. The mixture was stirredat RT for 1.5 h, and another load of NaBH₃CN (3.85 g, 58 mmol) was thenadded portionwise. The mixture was stirred for another 1.5 h, and thenpoured onto a saturated aq. solution of NaHCO₃. The pH was adjusted to8, and the mixture was then extracted with AcOEt. The combined org.layers were dried over Na₂SO₄, filtered and concentrated in vacuo togive the title compound (39.5 g) as an orange oil that was used as it isin the next step. UPLC-MS: MS 346.1 (M+H⁺); UPLC rt 0.66 min.

Step 3. ethyl2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

A mixture of ethyl 2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(39.5 g, 114 mmol), Boc-Gly-OH (20.1 g, 114 mmol) and Et₃N (32 mL, 230mmol) in AcOEt (570 mL) was treated with a solution of T3P in DMF (80mL, 137 mmol)—exothermic. The mixture was stirred at RT for 15 h and H₂O(200 mL) was then added. The pH was adjusted to 8 by addition ofsaturated aq. solution of NaHCO₃, and the aq. phase was extracted withAcOEt. The combined org. phases were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(57.4 g) that was used as it is in the next step. UPLC-MS: MS 503.2(M+H⁺); UPLC rt 1.20 min.

Step 4. sodium2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

To an orange solution of ethyl2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(57.4 mmol, 114 mmol) in EtOH (800 mL) was added an aqueous solution ofNaOH (4M, 33 mL, 132 mmol) and the mixture was stirred at RT for 60 h.The mixture was then filtered and the filter cake was washed with Et₂O.The filtrate was then concentrated down in vacuo until the formation ofanother precipitate. The mixture was then filtered again and the filtercake washed with Et₂O. The combined filter cakes were then dried invacuo to give the title compound (49.8 g) as a beige powder that wasused as it is in the next step. UPLC-MS: MS 475.2 (M+H⁺); UPLC rt 1.00min.

Step 5.2-(1-(carboxymethyl)-5-iodo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminiumchloride

A suspension of sodium2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(49.8 g, 100 mmol) in dry dioxane (1 L) was treated with an aqueoussolution of HCl (4M, 280 ml, 1.12 mol) and the mixture was stirred at RTfor 18 h. The reaction mixture was then concentrated in vacuo to givethe title compound (46.1 g) as a beige powder that was used as it is inthe next step. UPLC-MS: MS 375.1 (M+H⁺); UPLC rt 0.60 min.

Step 6.9-iodo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

A suspension of2-(1-(carboxymethyl)-5-iodo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminiumchloride (46.1 g, 112 mmol) and Et₃N (95 mL, 682 mmol) in dry DMF (1.1L) was treated with a solution of T3P in DMF (98 mL, 169 mmol)exothermic. The mixture was stirred at RT overnight. The mixture wasthen concentrated in vacuo and the residue obtained was taken up inAcOEt and diluted with an saturated aq. solution of NaHCO₃. The aqueousphase was extracted with AcOEt and the combined org. layers were thenwashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give a brown solid. The crude product obtained was suspended in MeOHand filtered. The filter cake was washed with MeOH and DCM, and thendried in vacuo to give the title compound (12.4 g) as a beige powderthat was used as it is in the next step. UPLC-MS: MS 357.1 (M+H⁺); UPLCrt 0.73 min.

Step 7.9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

A mixture of9-iodo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(15.5 g, 43 mmol), SeO₂ (9.63 g, 87 mmol) in pyridine (650 mL) washeated to 160° C. for 20 min in a microwave reactor. The mixture wasthen concentrated in vacuo and the residue obtained was taken up inAcOEt (10 and diluted with H₂O (1 L). The org. layer was separated andthe aqueous layer was extracted with AcOEt. The combined AcOEt phaseswere then dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by flash chromatography (SiO₂, Heptane to AcOEt to DCM/MeOH9:1) gave 7.25 g of beige solid. The aqueous phase was then extractedagain with DCM and the combined org. layers were dried over Na₂SO₄,filtered and concentrated in vacuo. Purification of the residue obtainedby flash chromatography (SiO₂, Heptane to AcOEt to AcOEt/MeOH 50:1) gave1.15 g of brownish solid. The two solids obtained were then combined andcrystallize form Et₂O to provide the title compound (8.15 g) as a beigesolid. UPLC-MS: MS 355.0 (M+H⁺); UPLC rt 0.78 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.83 (t, J=6.06 Hz, 2H); 3.76 (d, J=5.47 Hz, 4H); 6.36(s, 1H); 7.07 (t, J=7.82 Hz, 1H); 7.90 (d, J=7.43 Hz, 2H); 8.28 (br. s.,1H).

Following the procedure described above for Preparation 14 andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediates of the present invention were prepared:

Preparation 15:9-chloro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 263.0 (M+H⁺); UPLC rt 0.75 min.

Preparation 16:9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 259.2 (M+H⁺); UPLC rt 0.67 min.

Preparation 17:9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

Step 1. methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate

To a stirred solution of 5-bromoisoquinoline (100 g, 481 mmol) in DCM(1900 mL) acetyl chloride (35.9 mL, 505 mmol) was dropped at RT and thesolution was stirred for 60 min. The solution was cooled to −78° C.(yellow suspension) and then a solution oftert-butyl((1-methoxyvinyl)oxy)dimethylsilane (95 g, 505 mmol) in DCM(500 mL) was added in one portion. The resulting yellow solution wasstirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2Naqueous HCl (400 mL) was added and the reaction mixture was stirred for10 min. The organic layer was separated and washed with brine (2×). Thecombined organic layers were dried with sodium sulfate, filtered and thesolvent was removed under reduced pressure. The residue was dissolved indiethyl ether (1000 mL), charcoal was added and the mixture wasfiltrated through a pad of celite. The solvent was evaporated and thecrude product was dried under high vacuo overnight to yield the titlecompound (147 g) which was used without further purification. UPLC-MS:MS 324.0/326.0 (M+H⁺); UPLC rt 1.03 min.

Step 2. methyl2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

A stirred solution of methyl2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate (147 g, 453mmol), triethylsilane (388 g, 3333 mmol) and trifluoroacetic acid (266mL, 3446 mmol) in 1,2-dichloroethane (1100 mL) was stirred at 80° C. for3 h. The reaction mixture was cooled to rt and the solvent wasevaporated under reduced pressure. The remaining volatile componentswere evaporated under high vacuo and 40° C. bath temperature. To theresulting yellow residue saturated aqueous NaHCO₃ (500 mL) was addedwhile stirring and the mixture was extracted with DCM (3×400 mL). Theorganic layer was washed with saturated aqueous NaHCO₃ (300 mL) andbrine (300 mL). The organic layer was treated with charcoal, then driedwith sodium sulfate, filtered through a pad of Hyflo and the solvent wasremoved under reduced pressure. The crude product was crystallized fromdiethyl ether (300 mL) to yield the title compound as white crystals (90g). UPLC-MS: MS 326.0/328.0 (M+H⁺); UPLC rt 0.94 min.

Step 3. methyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

MeOH (1280 mL) was cooled to −15° C. and conc. Sulfuric acid (147 mL,2759 mmol) was added slowly (exotherm) under cooling. To this solution,methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(90 g, 276 mmol) was added and the reaction mixture was stirred underreflux for 96 h. The reaction mixture was cooled to RT and slowly addedto a solution of NaHCO₃ (540 g) in water (1.35 L). The slightly basicaqueous solution was extracted with AcOEt (3×500 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (300 mL) andbrine (300 mL). The organic layer was dried with sodium sulfate,filtered and the solvent was removed under reduced pressure. The crudeproduct was dried under high vacuo to yield the title compound as yellowfoam (76 g) which was used without further purification. UPLC-MS: MS284.1/286.1 (M+H⁺); UPLC rt 0.50 min.

Step 4. methyl2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

To a stirred solution of methyl2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (76 g, 267 mmol),Boc-glycine (51.5 g, 294 mmol) and triethylamine (74.6 mL, 535 mmol) inAcOEt (1350 mL), T3P (191 mL, 321 mmol, 50% m/m in AcOEt) was added andthe solution was stirred at RT for 90 min. 0.2N aqueous HCl (400 mL) wasadded and the reaction mixture was stirred for 5 min. The organic layerwas separated and washed with 0.2 N aqueous HCl (1×250 mL), saturatedaqueous NaHCO₃ (2×250 mL) and brine (1×250 mL). The combined organiclayers were dried with sodium sulfate, filtered and the solvent wasremoved under reduced pressure. The residue was dried under high vacuoovernight to yield the title compound as white foam (113 g) which wasused without further purification. UPLC-MS: MS 441.2/443.2 (M+H⁺); UPLCrt 1.12 min.

Step 5.2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid

To a stirred solution of methyl2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(113 g, 257 mmol) in EtOH (1000 mL), 4N aqueous NaOH (74.5 mL, 298 mmol)was added and the solution was stirred at RT for 2 h. The whiteprecipitate was filtered off and the white solid was washed with a smallamount of EtOH (1×) and diethyl ether (2×). The sodium salt waspartitioned between 0.5 N aqueous HCl and DCM, the organic layer wasseparated and washed with 0.5 N aqueous HCl (1×) and brine (1×). Thecombined organic layers were dried with sodium sulfate, filtered and thesolvent was removed under reduced pressure. The residue was dried underhigh vacuo overnight to yield the title compound as white foam (110 g).UPLC-MS: MS 427.2/429.2 (M+H⁺); UPLC rt 0.98 min.

Step 6.2-(5-bromo-1-(carboxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminiumchloride

To a stirred solution of2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid (110 g, 257 mmol) in dioxane (1290 mL), 4N HCl in dioxane (644 mL,2574 mmol) was added and the reaction mixture was stirred at RT for 24h. The white precipitate was filtered off and the white solid was washedwith a small amount of diethyl ether (2×). The HCl salt was dried underhigh vacuo overnight to yield the title compound as white solid (88 g).UPLC-MS: MS 327.1/329.1 (M+H⁺); UPLC rt 0.56 min.

Step 7.9-bromo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

To a stirred solution of2-(5-bromo-1-(carboxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminiumchloride (88 g, 242 mmol) and triethylamine (169 mL, 1210 mmol) in DCM(960 mL), T3P (212 mL, 363 mmol, 50% m/m in AcOEt) was added slowly(exotherm) and the suspension was stirred at rt for 1 h. The solvent wasreduced to a small amount under reduced pressure and the thicksuspension was treated with 2N aqueous HCl (500 mL). The whitesuspension was stirred at RT for 15 min and the solid was filtered off.The solid was again treated with 2N aqueous HCl (300 mL), stirred for 10min and filtered of. The slightly yellow solid was washed with water(1×) and with diethyl ether (2×). The resulting solid was dried at 50°C. under high vacuo overnight to yield the title compound as beige solid(71 g). UPLC-MS: MS 309.1/311.1 (M+H⁺); UPLC rt 0.72 min.

Step 8.9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

A mixture of9-bromo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(84.4 g, 273 mmol) and SeO₂ (53 g, 476 mmol) in pyridine (2400 mL),partitioned in 4 large scale microwave reactors, was stirred at 160° C.for 30 min under microwave conditions. The reaction mixture was allowedto warm to RT, filtered through a pad of celite and the solvent wasevaporated under reduced pressure. The residue was taken up in DCM andextracted with 0.25 N aqueous HCl (2×) and brine (1×). The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (1^(st) chromatography: 100%AcOEt; 2^(nd) chromatography: DCM/MeOH 95:5) to yield a yellow solid.The residue was triturated with diethyl ether to yield the titlecompound as slightly yellow crystals (25 g). UPLC-MS: MS 307.1/309.1(M+H⁺); UPLC rt 0.77 min.

Preparation 17a:9-bromo-10-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

Step 1. methyl2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate

To a stirred solution of 5-bromo-6-fluoroisoquinoline (43.9 g, 194 mmol)in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RTand the solution was stirred for 60 min. The solution was cooled to −78°C. (yellow suspension) and then a solution oftert-butyl((1-methoxyvinyl)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM(220 mL) was added in one portion. The resulting yellow solution wasstirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2Naqueous HCl was added and the reaction mixture was stirred for 10 min.The organic layer was separated and washed with brine (2×). The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The residue was dissolved in diethylether, charcoal was added and the mixture was filtrated through a pad ofcelite. The solvent was evaporated and the crude product was dried underhigh vacuo overnight to yield the title compound (70.6 g) which was usedwithout further purification. UPLC-MS: MS 342.2/344.2 (M+H⁺); UPLC rt1.05 min.

Step 2. methyl2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

A stirred solution of methyl2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate (70.6g, 206 mmol), triethylsilane (176 g, 1517 mmol) and trifluoroacetic acid(121 mL, 1568 mmol) in 1,2-dichloroethane (500 mL) was stirred at 80° C.for 3.5 h. The reaction mixture was cooled to rt and the solvent wasevaporated under reduced pressure. The remaining volatile componentswere evaporated under high vacuo and 40° C. bath temperature. To theresulting yellow residue saturated aqueous NaHCO₃ (500 mL) was addedwhile stirring and the mixture was extracted with DCM (3×400 mL). Theorganic layer was washed with saturated aqueous NaHCO₃ (250 mL) andbrine (200 mL). The organic layer was treated with charcoal, then driedwith sodium sulfate, filtered through a pad of Hyflo and the solvent wasremoved under reduced pressure. The crude product was crystallized fromdiethyl ether (200 mL) to yield the title compound as white crystals(47.6 g). UPLC-MS: MS 344.1/346.1 (M+H⁺); UPLC rt 0.95 min.

Step 3. methyl2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL,1383 mmol) was added slowly (exotherm) under cooling. To this solution,methyl2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(47.6 g, 138 mmol) was added and the reaction mixture was stirred underreflux for 96 h. The reaction mixture was cooled to RT and slowly addedto a solution of NaHCO₃ (244 g) in water (500 mL). The slightly basicaqueous solution was extracted with AcOEt (3×). The combined organiclayers were washed with saturated aqueous NaHCO₃ and brine. The organiclayer was dried with sodium sulfate, filtered and the solvent wasremoved under reduced pressure. The crude product was dried under highvacuo to yield the title compound as yellow foam (41.58 g) which wasused without further purification. UPLC-MS: MS 302.1/304.1 (M+H⁺); UPLCrt 0.51 min.

Step 4. methyl2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

To a stirred solution of methyl2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (41.58 g,138 mmol), Boc-glycine (26.5 g, 151 mmol) and triethylamine (38.4 mL,275 mmol) in AcOEt (690 mL), T3P (98 mL, 165 mmol, 50% m/m in AcOEt) wasadded and the solution was stirred at RT for 1 h. 0.2N aqueous HCl (200mL) was added and the reaction mixture was stirred for 5 min. Theorganic layer was separated and washed with 0.2N aqueous HCl (1×200 mL),saturated aqueous NaHCO₃ (2×200 mL) and brine (1×200 mL). The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The residue was dried under highvacuo overnight to yield the title compound as white foam (62.6 g) whichwas used without further purification. UPLC-MS: MS 459.3/461.3 (M+H⁺);UPLC rt 1.13 min.

Step 5.2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid

To a stirred solution of methyl2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate(62.6 g, 136 mmol) in EtOH (500 mL), 4N aqueous NaOH (39.5 mL, 158 mmol)was added and the solution was stirred at RT for 2 h. The whiteprecipitate was filtered off and the white solid was washed with a smallamount of EtOH (1×) and diethyl ether (2×). The sodium salt waspartitioned between 0.5N aqueous HCl and DCM, the organic layer wasseparated and washed with 0.5N aqueous HCl (1×) and brine (1×). Thecombined organic layers were dried with sodium sulfate, filtered and thesolvent was removed under reduced pressure. The residue was dried underhigh vacuo overnight to yield the title compound as white foam (58.45g). UPLC-MS: MS 445.2/447.2 (M+H⁺); UPLC rt 0.99 min.

Step 6.2-(2-(2-aminoacetyl)-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid (HCl salt)

To a stirred solution of2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid (58.45 g, 131 mmol) in dioxane (600 mL), 4N HCl in dioxane (328 mL,1313 mmol) was added and the reaction mixture was stirred at RT for 24h. The solvent was evaporated under reduced pressure and the HCl saltwas dried under high vacuo overnight to yield the title compound asyellow foam (54.6 g). UPLC-MS: MS 345.2/347.2 (M+H⁺); UPLC rt 0.56 min.

Step 7.9-bromo-10-fluoro-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

To a stirred solution of2-(2-(2-aminoacetyl)-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)aceticacid (HCl salt) (54.6 g, 143 mmol) and triethylamine (100 mL, 715 mmol)in DCM (570 mL), T3P (125 mL, 215 mmol, 50% m/m in AcOEt) was addedslowly (exotherm) and the suspension was stirred at rt for 1 h. Thesolvent was reduced to a small amount under reduced pressure and thethick suspension was treated with water (500 mL) and the suspension wasstirred overnight. The suspension was filtered off and the solid wasagain treated with water (200 mL), stirred for 10 min and filtered off.The slightly yellow solid was washed with water (1×) and with diethylether (2×). The resulting solid was dried at rt under high vacuoovernight to yield the title compound as slightly yellow solid (40.5 g).UPLC-MS: MS 327.1/329.1 (M+H⁺); UPLC rt 0.73 min.

Step 8.9-bromo-10-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

A mixture of9-bromo-10-fluoro-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(40.5 g, 124 mmol) and SeO₂ (24.1 g, 217 mmol) in pyridine (1240 mL) wasstirred at 130° C. for 4 h. The reaction mixture was allowed to warm toRT, filtered through a pad of celite and the solvent was evaporatedunder reduced pressure. The residue was taken up in DCM and extractedwith 1N aqueous HCl (2×) and brine (1×). The combined organic layerswere dried with sodium sulfate, filtered and the solvent was removedunder reduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera Four, eluent: 90% AcOEtin DCM for 40 min, then from 0% MeOH in DCM to 5% MeOH in DCM in 50 min,followed by 5% MeOH in DCM for 15 min). During evaporation the compoundcrystallized and yielded slightly orange crystals (9.3 g). UPLC-MS: MS325.2/327.2 (M+H⁺); UPLC rt 0.78 min.

Following the procedure described above for Preparation 17a andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediates of the present invention were prepared:

Preparation 17b (from 5-bromo-8-fluoroisoquinoline):9-bromo-12-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 325.1/327.1 (M+H⁺); UPLC rt 0.77 min.

Preparation 17c (from 5-bromo-7-fluoroisoquinoline):9-bromo-11-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 325.0/327.0 (M+H⁺); UPLC rt 0.79 min.

Following the procedure described above for Preparation 17 andsubstituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingintermediates of the present invention were prepared:

Preparation 18:9-(1H-pyrazol-1-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 295.1 (M+H⁺); UPLC rt 0.62 min.

Preparation 19:9-morpholino-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 314.0 (M+H⁺); UPLC rt 0.67 min.

Preparation 20:9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

UPLC-MS: MS 369.1 (M+H⁺); UPLC rt 0.84 min.

The following examples provide synthetic route to useful building blocksfor the preparation of compounds of the present invention.

Preparation 21: 5-(1H-pyrazol-1-yl)isoquinoline

A suspension of 5-hydrazinylisoquinoline (22.0 g, 112 mmol) in EtOH (300mL) was treated with 1,1,3,3-tetramethoxypropane (27.7 g, 169 mmol) andthe mixture was heated to 100° C. for 10 h. The reaction mixture wasthen concentrated in vacuo and the residue obtained taken up in DCM (500mL) and washed with a saturated aqueous solution of NaHCO₃—gasformation. The aqueous layer was extracted twice with DCM and thecombined org. layers were then dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, DCM/MeOH 95:5 to DCM/MeOH 9:1) to give the titlecompound (16.1 g). UPLC-MS: MS 196.1 (M+H⁺); UPLC rt 0.62 min.

Preparation 22: 4-(isoquinolin-5-yl)morpholine

A mixture of 5-bromoisoquinoline (4.07 g, 19.6 mmol), morpholine (3.41mL, 39.1 mmol), Cs₂CO₃ (12.75 g, 39.1 mmol), Pd(OAc)₂ (220 mg, 0.98mmol) and BINAP (609 mg, 0.98 mmol) in toluene (160 mL) was heated at110° C. for 6 h under N₂. The mixture was then concentrated in vacuo andthe black residue obtained was taken up in DCM and filtered over Celite.The filtrate was concentrated in vacuo and the brown oil obtained waspurified by flash chromatography (SiO₂, cHex to AcOEt) to give the titlecompound (4.17 g) as a brown oil. UPLC-MS: MS 215.1 (M+H⁺); UPLC rt 0.57min.

Preparation 23: methyl2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoate

Step 1: methyl 3-((2-iodophenethyl)amino)-2-methyl-3-oxopropanoate

A solution of T3P in AcOEt (50%, 26.2 mL, 44.0 mmol) was added dropwiseat 0° C. under N₂ to a clear solution of 2-(2-iodophenyl)ethanamine(9.45 g, 38.2 mmol), 3-methoxy-2-methyl-3-oxopropanoic acid (5.05 g,38.2 mmol) and Et₃N (10.7 mL, 76.0 mmol) in AcOEt (350 mL). The mixturewas stirred at RT for 6 days. A 2N aqueous solution of NaOH (50 mL) wasthen added to the reaction and the mixture was extracted with AcOEt. Thecombined org. layers were then dried over Na₂SO₄, filtered andconcentrated in vacuo. The yellow oil obtained was purified by flashchromatography (SiO₂, cHEx/AcOEt 100:0 to 50:50) to afford the titlecompound (10.83 g) as a clear oil. UPLC-MS: MS 362.2 (M+H⁺); UPLC rt0.95 min.

Step 2: methyl 2-(5-iodo-3,4-dihydroisoquinolin-1-yl)propanoate

A solution of methyl 3-((2-iodophenethyl)amino)-2-methyl-3-oxopropanoate(9.9 g, 27.4 mmol) in DCM (120 mL) was treated with oxalyl chloride(2.59 mL, 30.2 mmol) and the mixture was stirred at RT for 30 min. FeCl₃(5.34 g, 32.9 mmol) was then added portionwise at 0° C. and theresulting brown mixture was stirred at RT for 4 h. A 2N aqueous solutionof HCl (35 mL) was then added and the mixture was stirred at RT foranother 2 h. The mixture was then diluted with H₂O and extracted withDCM. The combined org. phases were then dried over Na₂SO₄, filtered andconcentrated in vacuo. The brown residue obtained was taken up in a 19:1mixture of MeOH/H₂SO₄ (120 mL) and stirred at reflux for 3 h. Themixture was then concentrated in vacuo and the brown reside obtained wastaken up in H₂O. The mixture was rendered basic with ammonia and thenextracted with AcOEt. The combined org. phases were dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by flash chromatography(SiO₂, cHex/AcOEt 100:0 to 70:30) gave the title compound (1.15 g) asyellow oil. UPLC-MS: MS 344.1 (M+H⁺); UPLC rt 0.96 min.

Step 3: methyl 2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)propanoate

A mixture of methyl 2-(5-iodo-3,4-dihydroisoquinolin-1-yl)propanoate(1.15 g, 3.35 mmol) in glacial AcOH (12 mL) was treated with NaBH₃CN(421 mg, 6.70 mmol) at RT under N₂. The mixture was stirred at RT for 16h, and then poured onto H₂O. The mixture was rendered basic with a 50%aqueous solution of NaOH and extracted with AcOEt. The combined org.phases were then dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (1.17 g) that was used as it is. UPLC-MS: MS346.1 (M+H⁺); UPLC rt 0.65 min.

Preparation 24: (S)-4-(1-methoxyethyl)-1H-imidazole; Preparation 25:(R)-4-(1-methoxyethyl)-1H-imidazole

Chiral resolution of racemic 4-(1-methoxyethyl)-1H-imidazole (17.3 g,137 mmol) by preparative HPLC (column: Chiralpak AD 20 μm, 5×50 cm;eluent: n-heptane:1-propanol:MeOH 90:6:4; flow 50 mL/min; UV detectionat 220 nm) yielded the title compounds.

Peak 1 (first eluted): 8.2 g (>98% ee) of(S)-4-(1-methoxyethyl)-1H-imidazole

UPLC-MS: MS127.1 (M+H⁺); UPLC rt 0.25 min.

chiral LC: instrument Shimadzu SCL 10A, injection volume 5 μL, flow rate1 mL/min, column AD 10 μM 4.6×250 mm, UV detection at 220 nm, eluent:n-heptane/n-propanol/MeOH 90:6:4, rt 5.39 min.

Peak 2 (second eluted): 7.8 g (>98% ee) of(R)-4-(1-methoxyethyl)-1H-imidazole

UPLC-MS: MS127.1 (M+H⁺); UPLC rt 0.25 min.

chiral LC: instrument Shimadzu SCL 10A, injection volume 5 μL, flow rate1 mL/min, column AD 10 μM 4.6×250 mm, UV detection at 220 nm, eluent:n-heptane/n-propanol/MeOH 90:6:4, rt 6.43 min.

The absolute configuration of both enantiomers were determined by X-rayanalysis.

Preparation 26: 4-cyclobutyl-1H-imidazole

A mixture of 2-bromo-1-cyclobutylethanone (27.2 g, 154 mmol) andformamidine acetate (80.0 g, 768 mmol) in ethyleneglycol (150 mL) washeated to 135° C. for 18 h. The mixture was then diluted with H₂O andthen continuously extracted with Et₂O for 18 h. The org. phase was thendried over Na₂SO₄, filtered and concentrated in vacuo. Purification bydistillation in a Kugelrohr oven and flash chromatography (SiO₂, DCM toDCM/MeOH 9:1) afforded the title compound (3.5 g). UPLC-MS: MS 123.1(M+H⁺); UPLC rt 0.36 min.

Preparation 27: 5-methyl-2-(tributylstannyl)oxazole

A solution of 5-methyloxazole (5.0 g, 60.2 mmol) in Et₂O (100 mL) wascooled to −78° C. under N₂ and treated with a 1.6 M solution of BuLi inhexane (41.4 mL, 66.2 mmol) dropwise. The mixture was stirred at −78° C.for 30 min and a solution of Bu₃SnCl (16.31 mL, 60.2 mmol) in Et₂O (50mL) was then added dropwise. The mixture was stirred at −78° C. foranother 30 min and then allowed to warm to RT. The reaction mixture wasfiltered on celite, and the filtrate concentrated in vacuo. Purificationby distillation (0.1 Torr, 128-130° C.) afforded the title compound (3.5g) as a yellow liquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (m,12H) 1.14-1.22 (m, 6H) 1.27-1.38 (m, 6H) 1.52-1.61 (m, 6H) 2.17-2.21 (m,3H) 7.49-7.54 (m, 1H).

Preparation 28: 4-(((tert-butyldiphenylsilynoxy)methyl)-1H-imidazole

A solution of (1H-imidazol-4-yl)methanol (14.6 g, 108 mmol) in DMF (100mL) was treated with imidazole (22.16 g, 325 mmol) and TBDPSCl (29.8 g,108 mmol) and the mixture was stirred and heated to 50° C. for 6 h. Itwas then allowed to cool to RT, poured onto H₂O and extracted with DCM.The combined org. layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO2,DCM/MeOH 100:0 to 90:10) afforded the title compound (35.3 g). UPLC-MS:MS 337.2 (M+H⁺); UPLC rt 1.04 min.

Preparation 29: 5-(1H-imidazol-4-yl)oxazole

Step 1: 5-(1-trityl-1H-imidazol-4-yl)oxazole

A mixture of 1-trityl-1H-imidazole-4-carbaldehyde (25.0 g, 73.9 mmol),TosMIC (14.42 g, 73.9 mmol) and K₂CO₃ (10.21 g, 73.9 mmol) in MeOH (750mL) was heated to reflux for 3 h. The mixture was then allowed to coolto RT, diluted with H₂O, and extracted with AcOEt. The combined org.layers were then washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO2,heptane/AcOEt 100:0 to 0:100) gave the title compound (14.6 g). UPLC (2min) rt 1.415 min.

Step 2: 5-(1H-imidazol-4-yl)oxazole

A solution of 5-(1-trityl-1H-imidazol-4-yl)oxazole (14.5 g, 38.4 mmol)was treated with a 90% aq. solution of formic acid (90 mL) and themixture was stirred at RT for 18 h. The mixture was then diluted withDCM, and washed with H2O and sat. aq. solution of NaHCO₃. The combinedaqueous layers were washed with DCM and then concentrated in vacuo. Theresidue obtained was placed in a Soxlet apparatus and continuouslyextracted with DCM for 12 h. The organic phase was then concentrated andthe crude product was crystallized in DCM to give the title compound(2.68 g). UPLC-MS: MS 136.1 (M+H⁺); UPLC rt 0.25 min.

Preparation 30: 5-(1H-imidazol-4-yl)isoxazole

Step 1:(E)-3-(dimethylamino)-1-(1-trityl-1H-imidazol-4-yl)prop-2-en-1-one

A mixture of 1-(1-trityl-1H-imidazol-4-yl)ethanone (81.0 g, 230 mmol)and DMF-DMA (77.0 mL, 575 mmol) in MeOH (500 mL) was heated to refluxfor 72 h. The mixture was then allowed to cool to RT and was then cooledto 0° C. the suspension was filtered and the filter cake was dried invacuo at 40° C. to give the title compound (72.7 g) that was used as itis in the next step. UPLC-MS: MS 408.3 (M+H⁺); UPLC rt 1.08 min.

Step 2: 5-(1H-imidazol-4-yl)isoxazole

A mixture of(E)-3-(dimethylamino)-1-(1-trityl-1H-imidazol-4-yl)prop-2-en-1-one (54.0g, 133 mmol) and HONH2*HCl (10.13 g, 146 mmol) in MeOH (800 mL) washeated to reflux for 18 h. The mixture was then allowed to cool to RTand was concentrated in vacuo. The residue obtained was taken up in DCMand washed with H₂O. The org. phase was then dried over Na₂SO₄, filteredand concentrated in vacuo. The residue obtained was stirred in Et₂O, andthe suspension was filtered. The filter cake was dried in vacuo at 40°C. The aqueous phase was then concentrated in vacuo and the residueobtained was placed in a Soxlet apparatus and continuously extractedwith DCM for 36 h. The organic phase was then concentrated in vacuo andthe residue obtained was stirred in DCM. The suspension was thenfiltered and the filter cake was dried in vacuo at 40° C. The two filtercakes were then crystallized in AcOEt to give the title compound (5.44g). UPLC-MS: MS 136.1 (M+H+); UPLC rt 0.33 min.

Preparation 31:4-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-1H-imidazole

Step 1: 1-(1-trityl-1H-imidazol-4-yl)cyclopropanol

A solution of methyl 1-trityl-1H-imidazole-4-carboxylate (11.0 g, 29.9mmol) and Ti(OiPr)₄ (12.37 mL, 41.8 mmol) in THF (3 mL) was treateddropwise with a 1M solution of EtMgBr (76 mL, 76 mmol) to maintain thetemperature below 35° C. The mixture was then stirred at RT for 4 h, andthen poured onto H₂O. The precipitate was filtered off, and the filtratewas extracted with AcOEt. The combined org. layers were dried overNa₂O₄, filtered and concentrated in vacuo. Purification by flashchromatography (SiO₂, AcOEt/heptane 30:70 to 100:0) gave the titlecompound (440 mg). UPLC-MS: MS 367.3 (M+H⁺); UPLC rt 1.01 min.

Step 2: 1-(1H-imidazol-4-yl)cyclopropanol

A mixture of 1-(1-trityl-1H-imidazol-4-yl)cyclopropanol (2.4 g, 6.55mol) was treated with a 90% aq. solution of formic acid (50 mL) and themixture was stirred at RT for 24 h. The mixture was then concentrated invacuo, diluted in a small volume of MeOH, and the solution was renderedbasic with a 7M solution of NH3 in MeOH. The white precipitate wasfiltered off and the filtrate was concentrated in vacuo. Purification byflash chromatography (SiO₂, DCM/MeOH 100:0 to 85:15) afforded the titlecompound (920 mg). UPLC-MS: MS 125.1 (M+H+).

Step 3: 4-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-1H-imidazole

A solution of 1-(1H-imidazol-4-yl)cyclopropanol (700 mg, 5.64 mmol) inDMF (1 mL) was treated with imidazole (768 mg, 11.28 mmol) and TBSCl(935 mg, 6.20 mmol) and the mixture was stirred at RT for 2 h. Themixture was then poured onto H₂O, and extracted with AcOEt. The combinedorg. layers were dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (850 mg) that was used as it is. UPLC-MS: MS239.2 (M+H+); UPLC rt 0.82 min.

Preparation 32: 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1H-imidazole

A solution of 2-(1H-imidazol-4-yl)ethanol (1.24 g, 11.1 mmol) in DMF (10mL) was treated with imidazole (1.51 g, 22.1 mmol) and TBDPSCl (3.12 mL,12.2 mmol) and the mixture was stirred at RT for 2 h. The mixture wasthen poured onto H₂O and extracted with AcOEt. The combined org. layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby flash chromatography (SiO₂, AcOEt/heptane 0:100 to 100:0) gave thetitle compound (1.6 g). UPLC-MS: MS 351.2 (M+H+); UPLC rt 1.02 min.

Preparation 33: 3-(1H-imidazol-4-yl)oxetan-3-ol

Step 1. 3-(1-benzyl-1H-imidazol-4-yl)oxetan-3-ol

A solution of 1-benzyl-4-iodo-1H-imidazole (6.0 g, 21.12 mmol) in DCM(80 mL) was treated with EtMgBr (3M in ether, 7.74 mL, 23.23 mmol) at rtand the mixture was stirred at RT overnight. The mixture was then pouredonto saturated aqueous NH₄Cl solution and extracted with DCM. Thecombined org. layers were dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was purified by flash-column chromatographyover silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min,then from 1% MeOH in DCM to 5% MeOH in DCM in 25 min, followed by 5%MeOH in DCM for 6 min). The residue was crystallized from EtOAc to yieldthe title compound as white crystals (2.35 g). UPLC-MS: MS 231.1 (M+H⁺);UPLC rt 0.43 min.

Step 2. 3-(1H-imidazol-4-yl)oxetan-3-ol

A solution of 3-(1-benzyl-1H-imidazol-4-yl)oxetan-3-01 (2.35 g, 10.21mmol), 10% Pd/C (600 mg, 1.02 mmol) in MeOH (85 mL) was hydrogenated for20 h at rt. The catalysator was filtered off and the solvent was removedin vacuo to yield the title compound as beige crystals (1.43 g).UPLC-MS: MS 141.1 (M+H⁺); UPLC rt 0.17 min.

Example 19-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1.(Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethanimine.1-1

A flask was charged with 5-methoxy-1-methyl-3,4-dihydroisoquinoline (3.0g, 17.1 mmol) and Et₂O (100 mL) under N₂ and cooled to 30° C. A 2Msolution of LDA (8.56 mL, 17.1 mmol) was added dropwise. The resultingbrown suspension was stirred for 30 min at this temperature, and thencooled to −78° C. A solution of 3-methoxybenzonitrile (2.28 g, 17.1mmol) in Et₂O (25 mL) was added dropwise. The mixture was stirred at−78° C. for 1 h, and then allowed to warm to RT and stirred for another18 h. the mixture was then poured onto H₂O and extracted with AcOEt. Theorg. layers were dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (5.9 g) as a brown oil that was used as it isin the next step. UPLC-MS: MS 309.3 (M+H⁺); UPLC rt 0.73 min.

Step 2. ethyl2-((E)-((Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethylidene)amino)acetate.1-2

A mixture of 1-1 (5.8 g, 18.81 mmol) and glycine ethyl esterhydrochloride (13.1 g, 94 mmol) in EtOH (200 mL) was heated to 100° C.and stirred for 2 h. The reaction was then cooled to RT and the mixturewas concentrated in vacuo. The residue obtained was taken up in DCM andwashed with a 1 M aq. solution of NaOH. The org. layer was then driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (7.0 g) as a brown oil that was used as it is in the next step.UPLC-MS: MS 395.3 (M+H⁺); UPLC rt 0.80 min.

Step 3.9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 1

A solution of 1-2 (6.9 g, 17.5 mmol) in EtOH (200 mL) was treated with asolution of NaOEt in EtOH (21 wt. %, 32.7 mL, 87 mmol) and the mixturewas stirred at RT for 2 h. The reaction was then concentrated in vacuoand the residue taken up in DCM. The organic phase was washed with a 1Naq. solution of NaOH, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product obtained was purified by flash chromatography(SiO₂, hexan to hexane/AcOEt 1:1) to give a red solid that wasrecrystallized from heptane/AcOEt to give the title compound (1.37 g) asa beige solid. MS 349.2 (M+H⁺). UPLC (2 min) rt 1.147 min. ¹H NMR (400MHz, CHLOROFORM-d): δ ppm 2.87-2.97 (m, 2H); 3.86 (s, 3H); 3.88 (s, 3H);3.90-3.96 (br s, 2H); 4.45-4.56 (br s, 2H); 6.94 (d, J=7.82 Hz, 1H);7.00 (dd, J=8.02, 2.93 Hz, 1H); 7.04 (s, 1H); 7.29-7.40 (m, 4H);7.42-7.52 (m, 1H).

Following the procedure described above for Example 1 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 29-chloro-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 329.1 (M+H⁺); UPLC rt 1.09 min.

Example 39-chloro-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 353.1 (M+H⁺). UPLC (3.5 min) rt 1.195 min.

Example 42-(thiophen-2-yl)-9-(trifluoromethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 363.2 (M+H⁺); UPLC rt 1.12 min.

Example 59-methoxy-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 325.2 (M+H⁺); UPLC rt 0.95 min.

Example 69-chloro-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 354.3 (M+H⁺); UPLC rt 1.11 min.

Example 79-methoxy-2-(5-methylfuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 323.2 (M+H⁺). UPLC (3.5 min) rt 0.896 min.

Example 89-methoxy-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 350.2 (M+H⁺). UPLC (2 min) rt 1.098.

Example 99-methoxy-2-(6-methoxypyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 350.2 (M+H⁺); UPLC rt 1.12 min.

Example 102-(2-ethylpyridin-4-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 348.5 (M+H⁺); UPLC rt 1.04 min.

Example 119-methoxy-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 323.1 (M+H⁺); UPLC rt 0.77 min.

Example 129-methoxy-2-(3-(2-methoxyethoxy)phenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 393.5 (M+H⁺); UPLC rt 0.89 min.

Example 1310-chloro-9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 383.1 (M+H⁺); UPLC rt 1.06 min.

Example 1411-chloro-9-methoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS383.1 (M+H⁺); UPLC rt 1.35 min.

Example 152-(3-ethoxyphenyl)-9-methoxy-7-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 377.2 (M+H); UPLC rt 1.12 min.

Example 169-methoxy-2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 387.2 (M+H⁺). UPLC (3.5 min) rt 1.477 min.

Example 179-methoxy-2-(4-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 349.2 (M+H⁺); UPLC rt 0.84 min.

Example 189-methoxy-2-(5-methoxy-2-methylphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 363.2 (M+H⁺). UPLC (3.5 min) rt 1.115 min.

Example 199-fluoro-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 313.2 (M+H⁺); UPLC rt 0.97 min.

Example 209-bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 397.2 (M+H⁺); UPLC rt 1.09 min.

Example 212-(2-(dimethylamino)pyridin-4-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 363.1 (M+H⁺); UPLC rt 0.85 min.

Example 222-(2-methoxypyridin-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 405.1 (M+H⁺); UPLC rt 0.96 min.

Example 232-(5-methylfuran-2-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 378.1 (M+H⁺); UPLC rt 0.70 min.

Example 242-(1-methyl-1H-pyrazol-3-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 378.1 (M+H⁺); UPLC rt 0.64 min.

Example 252-(1-methyl-1H-pyrazol-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 378.2 (M+H⁺). UPLC (3.5 min) rt 0.771 min.

Example 269-(2-hydroxypropan-2-yl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 0.84 min.

Example 279-(2-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 351.1 (M+H⁺); UPLC rt 0.65 min.

Example 282-(furan-2-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 356.0 (M+H⁺); UPLC rt 0.65 min.

Example 299-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 373.1 (M+H⁺); UPLC rt 1.09 min.

Example 309-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 445.4 (M+H⁺); UPLC rt 1.32 min.

Example 319-iodo-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 419.0 (M+H⁺); UPLC rt 1.01 min.

Example 329-iodo-2-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 419.1 (M+H⁺); UPLC rt 0.75 min.

Example 339-iodo-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 446.2 (M+H⁺); UPLC rt 1.13 min.

Example 342-(furan-3-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 405.0 (M+H⁺); UPLC rt 0.94 min.

Example 359-iodo-2-(1-isopropyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 447.2 (M+H⁺); UPLC rt 0.86 min.

Example 369-iodo-2-(1-methyl-1H-imidazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 419.0 (M+H⁺); UPLC rt 0.69 min.

Example 36a9-methoxy-2-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 391.1 (M+H⁺); UPLC rt 0.95 min.

Example 379-ethyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1.2-(3-methoxyphenyl)-9-((trimethylsilyl)ethynyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.37-1

A mixture of9-bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 20) (1.0 g, 2.52 mmol), Pd(PPh₃)₂Cl₂ (88 mg, 0.13 mmol) and CuI(48 mg, 0.25 mmol) in piperidine (15 mL) was degassed (sonication) witha flux of Ar, and trimethylsilylacetylene (1.06 mL, 7.55 mmol) was thenadded. The mixture was heated to 80° C. for 18 h. Additionaltrimethylsilylacetylene (1.00 mL, 7.12 mmol) and Pd(PPh₃)₂Cl₂ (88 mg,0.13 mmol) were added and the mixture was heated to 80° C. for another24 h. After cooling to RT, the reaction was diluted with AcOEt, andwashed with H₂O. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO₂,hexane to hexane/AcOEt 1:1) afforded the title compound (700 mg) as abrown solid UPLC-MS: MS 415.3 (M+H⁺); UPLC rt 1.43 min.

Step 2.9-ethynyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.40-2

A solution of 37-1 (700 mg, 1.69 mmol) in MeOH (20 mL) was treated withK₂CO₃ (467 mg, 3.38 mmol) and the mixture was stirred at RT for 18 h.The mixture was concentrated in vacuo, and the residue taken up in AcOEtand washed with H₂O. The organic layer was then dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product wasre-crystallized from heptane/AcOEt to provide the title compound (410mg) as brown crystals. UPLC-MS: MS 343.3 (M+H⁺); UPLC rt 1.03 min.

Step 3.9-ethyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 37

A mixture of 37-2 (200 mg, 0.58 mmol), Pd/C (10%, 100 mg, 0.94 mmol) inTHF (20 mL) was stirred at RT for 5 h under an atmosphere of H₂. Themixture was then filtered and concentrated in vacuo. Purification byflash chromatography (SiO₂, hexane to hexane/AcOEt 1:1) gave the titlecompound (160 mg) as a yellow solid. MS 347.2 (M+H⁺). UPLC (2 min) rt1.263 min. ¹H NMR (400 MHz, CHLOROFORM-d): 6 ppm 2.87-2.97 (m, 2H); 3.86(s, 3H); 3.88 (s, 3H); 3.90-3.96 (br s, 2H); 4.45-4.56 (br s, 2H); 6.94(d, J=7.82 Hz, 1H); 7.00 (dd, J=8.02, 2.93 Hz, 1H); 7.04 (s, 1H);7.29-7.40 (m, 4H); 7.42-7.52 (m, 1H).

Following the procedure described above for Example 37 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 389-ethynyl-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

MS 319.0 (M+H+). UPLC (2 min) rt 1.086 min.

Example 395-oxo-2-(thiophen-2-yl)-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carbonitrile

A microwave flask was charged with9-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 29) (145 mg, 0.39 mmol), Zn(CN)₂ (191 mg, 1.63 mmol) andPd(PPh₃)₄ (47 mg, 0.041 mmol) in DMF (4 mL) was heated to 170° C. for 18h. The reaction was allowed to cool to RT, taken up in AcOEt and washedwith H₂O. The org. layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, hexane to hexan/AcOEt 1:1) and prep. HPLC (column:RP-C18 sunfire, 5 μm, 100×300 mm; solvent A: H₂O+0.1% TFA; solvent BCH₃CN; gradient (% B): 10-30% in 16 min; 50 mL/min). The productobtained was passed onto a SPE cartridge to release the free base, andthe residue obtained was triturated in heptane/AcOEt to give the titlecompound (8 mg) as a yellow solid. UPLC-MS: MS 320.2 (M+H⁺); UPLC rt0.87 min. ¹H NMR (600 MHz, DMSO-d₆): δ ppm 3.07 (t, J=5.55 Hz, 2H); 3.87(br. s., 2H); 4.29 (br. s., 2H); 7.11 (t, J=4.14 Hz, 1H); 7.51 (s, 1H);7.56 (t, J=7.87 Hz, 1H); 7.66 (d, J=4.24 Hz, 2H); 7.93 (d, J=7.47 Hz,1H); 8.42 (d, J=8.07 Hz, 1H).

Following the procedure described above for Example 39 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 402-(1-methyl-1H-pyrazol-3-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carbonitrile

UPLC-MS: MS 318.2 (M+H⁺); UPLC rt 0.66 min.

Example 412-(3-methoxyphenyl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A solution of Pd(OAc)₂ (4.0 mg, 0.017 mmol), and BINAP (10.5 mg, 0.017mmol) in toluene (5 mL) was stirred at RT under N₂ for 10 min, and thentransferred to a mixture of9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 30) (150 mg, 0.34 mmol), morpholine (35 μL, 0.41 mmol) andCs₂CO₃ (550 mg, 1.69 mmol) in toluene (5 mL). The reaction was stirredat RT under N₂ for 5 min, and then heated to reflux for 24 h. Themixture was allowed to cool to RT, and then filtered and concentrated invacuo. The crude product was purified by flash chromatography (SiO₂,hexane to hexane/AcOEt 1:1) and the brown solid obtained wasrecrystallized from hexane to give the title compound (83 mg) as a beigesolid. UPLC-MS: MS 404.5 (M+H⁺); UPLC rt 1.09 min. ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 2.84-3.03 (m, 6H); 3.76-3.95 (m, 6H); 3.87 (s, 3H);4.51 (br. s., 2H); 6.92 (s, 1H); 7.00 (dd, J=8.21, 2.74 Hz, 1H); 7.14(d, J=7.82 Hz, 1H); 7.28-7.51 (m, 5H).

Following the procedure described above for Example 41 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 422-(1-isopropyl-1H-pyrazol-4-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 387.1 (M+H⁺); UPLC rt 0.70 min.

Example 439-((dimethylamino)methyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1.9-(hydroxymethyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.43-1

A mixture of-bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 20) (1.50 g, 3.78 mmol), (tributylstannyl)methanol (1.52 g,4.72 mmol) and Pd(PPh₃)₄ (436 mg, 0.38 mmol) in dioxane (15 mL) washeated to 120° C. for 1 h in a microwave reactor. The reaction was thenfiltered and the filtrate concentrated in vacuo. The residue obtainedwas purified by flash chromatography (SiO₂, DCM to DCM/MeOH 95:5) togive a beige solid, which was then triturated in Et₂O. The suspensionwas filtered and the filter cake was dried in vacuo to give the titlecompound (652 mg) as a beige solid. UPLC-MS: MS 349.4 (M+H⁺); UPLC rt0.83 min. ¹H NMR (400 MHz, CHLOROFORM-d): 6 ppm 2.06 (br s, 1H); 3.01(t, J=6.06 Hz, 2H); 3.85 (s, 3H); 3.92 (t, J=6.26 Hz, 2H); 4.49 (br. s.,2H); 4.76 (s, 2H); 6.96 (s, 1H); 7.00 (dd, J=8.02, 2.54 Hz, 1H);7.27-7.41 (m, 3H); 7.41-7.52 (m, 2H); 7.66 (d, J=7.82 Hz, 1H).

Step 2:9-((dimethylamino)methyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 43

A solution of 43-1 (200 mg, 0.57 mmol) and Et₃N (0.12 mL, 0.86 mmol) inDCM (10 mL) under N₂ was cooled to 0° C. and methanesulfonyl chloride(54 μL, 0.69 mmol) was added dropwise. The mixture was stirred at 0° C.for 30 min and then diluted with DCM and washed with H₂O. The org. layerwas dried over Na₂SO₄, filtered and concentrated in vacuo to afford ayellow oil that as diluted in THF (5 mL). A 2M solution of Me₂NH in THF(0.29 mL, 0.58 mmol) was then added dropwise and the mixture was stirredat RT for 2 h. The mixture was then concentrated in vacuo and theresidue obtained was purified by flash chromatography (SiO₂, hexane tohexane/AcOEt 1:1, followed by DCM to DCM/MeOH 95:5) to give a brown oilthat solidify upon standing. Recrystallization from heptane afforded thetitle compound (49 mg) as a beige solid. UPLC-MS: MS 376.5 (M+H⁺); UPLCrt 0.66 min. ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.24 (s, 6H); 3.06(t, J=5.87 Hz, 2H); 3.43 (s, 2H); 3.85 (s, 3H); 3.90 (t, J=6.26 Hz, 2H);4.50 (br. s., 2H); 6.96 (s, 1H); 6.99 (dd, J=8.02, 2.54 Hz, 1H);7.27-7.46 (m, 5H); 7.62 (d, J=7.43 Hz, 1H).

Following the procedure described above for Example 43 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 449-((2-methoxyethoxy)methyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 407.1 (M+H⁺); UPLC rt 0.86 min.

Example 459-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 323.1 (M+H⁺); UPLC rt 0.52 min.

Example 469-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 323.1 (M+H⁺); UPLC rt 0.49 min.

Example 479-(1-methoxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1.9-acetyl-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.47-1

A mixture of9-iodo-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 31) (2.0 g, 4.78 mmol), tributyl(1-ethoxyvinyl)stannane (2.02mL, 5.98 mmol) and Pd(PPh₃)₄ (276 mg, 0.24 mmol) in 1,4-dioxane (15 mL)was heated to 140° C. for 90 min. The mixture was then filtered andconcentrated in vacuo and the residue obtained was purified by flashchromatography (SiO₂, DCM to DCM/MeOH 95:5). The brown oil obtained wastaken up in THF (100 mL) and treated with a 0.1 N aq. solution of HCl(48 mL, 4.78 mmol). The mixture was stirred at RT for 90 min. Themixture was then diluted with AcOEt and washed with a saturated aq.solution of NaHCO₃. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The residue obtained was purified by flashchromatography (SiO₂, DCM to DCM/MeOH 95:5) to give a brown oil that wassuspended in Et₂O. The suspension was filtered and the filter cake wasdried in vacuo to give the title compound (912 mg) as a yellow solid.UPLC-MS: MS 335.0 (M+H⁺); UPLC rt 0.62 min. ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 2.62 (s, 3H); 3.24 (t, J=6.06 Hz, 2H); 3.81 (t,J=6.45 Hz, 2H); 3.92 (s, 3H); 4.49 (br. s., 2H); 6.81 (br. s., 1H); 7.17(s, 1H); 7.34-7.45 (m, 2H); 7.77 (d, J=7.82 Hz, 1H); 7.84 (d, J=7.82 Hz,1H).

Step 2.9-(1-hydroxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.47-2

A solution of 47-1 (400 mg, 1.20 mmol) in THF (30 mL) was treated withNaBH₄ (23 mg, 0.60 mmol) and the mixture was stirred at RT for 48 h. Themixture was then diluted with AcOEt, and washed with H₂O. The org. phasewas dried over Na₂SO₄, filtered and concentrated in vacuo. The residueobtained was purified by flash chromatography (SiO₂, DCM to DCM/MeOH95:5) to afford a yellow oil that was suspended in Et₂O. The suspensionwas filtered and the filter cake was dried on vacuo to give the titlecompound (145 mg) as a light yellow solid. UPLC-MS: MS 337.3 (M+H⁺);UPLC rt 0.60 min. ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.49 (d, J=6.26Hz, 3H); 1.82-1.96 (m, 1H); 2.86-3.09 (m, 2H); 3.75-3.99 (m, 2H); 3.92(s, 3H); 4.48 (d, J=12.12 Hz, 2H); 5.17 (d, J=3.52 Hz, 1H); 6.82 (br.s., 1H); 7.19 (s, 1H); 7.32-7.40 (m, 2H); 7.61 (d, J=7.82 Hz, 1H); 7.64(d, J=7.82 Hz, 1H).

Step 3.9-(1-methoxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 47

A solution of 47-2 (120 mg, 0.36 mmol) in trimethylorthoformate (2.0 mL,18.1 mmol) was treated with I₂ (55 mg, 0.22 mmol) and the mixture wasstirred at RT for 5 days. The mixture was then taken up in DCM andwashed with an aq. saturated solution of Na₂S₂O₃. The org. phase wasthen dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby flash chromatography (SiO₂, DCM to DCM/MeOH 9:1) gave a yellow oilthat re-crystallized from heptane to give the title compound (79 mg) asa white solid. UPLC-MS: MS 351.4 (M+H⁺); UPLC rt 0.73 min. ¹H NMR (400MHz, CHLOROFORM-d): δ ppm 1.42 (d, J=6.65 Hz, 3H); 2.91-3.05 (m, 2H);3.25 (s, 3H); 3.87 (t, J=6.26 Hz, 2H); 3.92 (s, 3H); 4.48 (br. s., 2H);4.56 (q, J=6.65 Hz, 1H); 6.81 (br. s., 1H); 7.19 (s, 1H); 7.31-7.39 (m,2H); 7.47 (d, J=7.82 Hz, 1H); 7.63 (d, J=7.82 Hz, 1H).

Following the procedure described above for Example 47 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 489-acetyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 361.1 (M+H⁺); UPLC rt 0.90 min.

Example 492-(3-methoxyphenyl)-9-phenyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A mixture of9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 30) (250 mg, 0.56 mmol), tributyl(phenyl)stannane (202 μL, 1.10mmol) and Pd(PPh₃)₄ (33 mg, 0.03 mmol) in 1,4-dioxane (4 mL) was heatedin a microwave reactor at 140° C. for 1 h. The mixture was then filteredand concentrated in vacuo. The crude product obtained was purified byflash chromatography (SiO₂, hexane to hexane/AcOEt 3:1) to give a yellowoil that was recrystallized from heptane to afford the title compound(144 mg) as white solid. UPLC-MS: MS 395.1 (M+H⁺); UPLC rt 1.20 min. ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 2.90 (t, J=6.06 Hz, 2H); 3.79 (t,J=6.26 Hz, 2H); 3.86 (s, 3H); 4.53 (br. s., 2H); 6.97 (s, 1H); 6.97-7.04(m, 1H); 7.28-7.37 (m, 3H); 7.37-7.51 (m, 7H); 7.68 (t, J=4.50 Hz, 1H).

Following the procedure described above for Example 49 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 502-(2-methoxypyridin-4-yl)-9-(pyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 397.1 (M+H⁺); UPLC rt 0.95 min.

Example 512-(furan-3-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 356.1 (M+H⁺); UPLC rt 0.65 min.

Example 522-(2-methoxypyridin-4-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 398.2 (M+H⁺); UPLC rt 0.91 min.

Example 539-(6-fluoropyridin-3-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 1.06 min.

Example 549-(3-fluoropyridin-4-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 0.98 min.

Example 552-(1-methyl-1H-imidazol-4-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 370.1 (M+H⁺); UPLC rt 0.48 min.

Example 562-(1-methyl-1H-pyrazol-3-yl)-9-(2-methylpyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 384.4 (M+H⁺); UPLC rt 0.60 min.

Example 572-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1.9-(4,5-dihydrofuran-2-yl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.57-1

A mixture of9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(Example 30) (1.0 g, 2.25 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane(1.21 g, 3.38 mmol) and Pd(PPh₃)₄ (0.13 g, 0.11 mmol) in 1,4-dioxane (10mL) was heated in a microwave reactor at 150° C. for 90 min. The mixturewas then diluted with AcOEt and filtered. The filtrate was concentratedin vacuo and the crude product obtained was purified by flashchromatography (SiO₂, heptane to heptane/AcOEt 1:1) to give a brownsolid, which was suspended in heptane and heated to reflux. Thesuspension was then allowed to cool to RT and then filtered. The filtercake was then dried in vacuo to afford the title compound (543 mg) as abeige solid. UPLC-MS: MS 387.2 (M+H⁺); UPLC rt 1.10 min.

Step 2.2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 57

A mixture of 57-1 (300 mg, 0.78 mmol) and Raney-Nickel (50 mg, 1.32mmol) in THF was evacuated in vacuo and placed under an atmosphere ofH₂. The process was repeated and the mixture was then stirred at RT for7 days under H₂. The reaction mixture was then filtered and concentratedin vacuo. The residue obtained was purified by flash chromatography(SiO₂, heptane to AcOEt) to afford the title compound (12 mg) as beigesolid. UPLC-MS: MS 389.3 (M+H⁺); UPLC rt 0.97 min. ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.72 (dq, J=12.27, 7.64 Hz, 1H); 2.05 (quin, J=7.14Hz, 2H); 2.32-2.44 (m, 1H); 2.82-3.06 (m, 2H); 3.71-3.84 (m, 1H); 3.86(s, 3H); 3.92-4.09 (m, 2H); 4.11-4.21 (m, 1H); 4.51 (br. s., 2H); 5.09(t, J=7.23 Hz, 1H); 6.94 (s, 1H); 7.00 (dd, J=8.21, 2.35 Hz, 1H);7.28-7.41 (m, 3H); 7.42-7.50 (m, 1H); 7.60 (dd, J=7.62, 3.71 Hz, 2H).

Example 589-methoxy-2-(6-oxo-1,6-dihydropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A mixture of9-methoxy-2-(6-methoxypyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneExample 9 (140 mg, 0.40 mmol), NaI (156 mg, 1.04 mmol), TMSCl (768 μL,6.01 mmol) in acetonitrile (10 mL) was heated to 100° C. for 4 days. Themixture was then diluted with AcOEt, washed with an aq. solution ofNa₂S₂O₃ (10%) and H₂O. The org. layer was then dried over Na₂SO₄,filtered and concentrated in vacuo. The residue obtained was suspendedin a small volume of DMF and the precipitate was filtered and washedwith Et₂O. The filter cake was dried in vacuo to afford Example 58 (16mg) as a beige solid. UPLC-MS: MS 336.4 (M+H⁺); UPLC rt 0.94 min. ¹H NMR(600 MHz, DMSO-d₆): δ ppm 2.92 (t, J=6.06 Hz, 2H); 3.86 (s, 3H); 3.93(t, J=6.26 Hz, 2H); 4.52 (s, 2H); 7.05 (d, J=8.27 Hz, 1H); 7.27 (d,J=8.28 Hz, 1H); 7.45 (t, J=8.07 Hz, 1H); 7.49 (s, 1H); 7.75 (d, J=8.07Hz, 1H); 7.79 (d, J=7.27 Hz, 1H); 7.88-7.94 (m, 1H).

Following the procedures described above and substituting theappropriate reagents, starting materials and purification methods knownto those skilled in the art, the following compounds of the presentinvention were prepared:

Example 599,10-dimethoxy-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 379.5 (M+H⁺); UPLC rt 0.87 min.

Example 609-methoxy-2-(2-oxo-1,2-dihydropyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 336.0 (M+H⁺); UPLC rt 0.84 min.

Example 612-(4-isopropyl-1H-imidazol-1-yl)-9-methoxy-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

To a stirred solution of9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(80 mg, 0.31 mmol) in 1,2-dichloroethane (8 mL) was added POCl₃ (0.058mL, 0.62 mmol) and the resulting yellow suspension was stirred at 100°C. for 1 h. The reaction mixture was cooled to RT and concentrated underreduced pressure to dryness. The resulting crude chloro compound wasdissolved in 1,2-dichloroethane (8 mL), 4-isopropyl-1H-imidazole (102mg, 0.93 mmol) was added and the mixture was stirred at 100° C. for 2 h.The reaction mixture was allowed to warm to RT. Saturated aqueous NaHCO₃solution was added and the mixture was extracted twice with DCM. Thecombined organic layers were dried with sodium sulfate, filtered and thesolvent was removed under reduced pressure. The crude product waspurified by flash-column chromatography over silicagel (eluent: gradient0% to 100% ethyl acetate/cyclohexane in 30 min) to yield 15 mg of abrown solid. Further purification by SFC (column: Diol 5 μm, 250×30 mm,60 A, Princeton; eluent: 13% MeOH/CO₂ for 0.5 min, then from 13%MeOH/CO₂ to 18% MeOH/CO₂ in 6 min; then from 18% MeOH/CO₂ to 50%MeOH/CO₂ in 1 min; flow 100 mL/min; UV detection at 220 nm) yielded thetitle compound (9 mg). UPLC-MS: MS 351.3 (M+H⁺); UPLC rt 0.90 min. ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 1.35 (d, J=6.8 Hz, 6H), 2.95 (t,J=6.2 Hz, 2H), 3.03-3.19 (m, 1H), 3.88 (s, 3H), 3.92-4.05 (m, 2H), 4.40(s, 2H), 6.87-7.05 (m, 2H), 7.19-7.58 (m, 4H).

Following the procedure described above for Example 61 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 629-chloro-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 326.9 (M+H⁺); UPLC rt 0.81 min.

Example 639-iodo-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 473.1 (M+H⁺); UPLC rt 1.14 min.

Example 641-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carbonitrile

UPLC-MS: MS 430.0 (M+H⁺); UPLC rt 1.01 min.

Example 652-(4-(hydroxymethyl)-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 435.2 (M+H⁺); UPLC rt 0.80 min.

Example 66 methyl1-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carboxylate

UPLC-MS: MS 463.1 (M+H⁺); UPLC rt 0.97 min.

Example 672-(2,4-dimethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 433.1 (M+H⁺); UPLC rt 0.78 min.

Example 68 ethyl1-(9-iodo-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carboxylate

UPLC-MS: MS 477.1 (M+H⁺); UPLC rt 1.02 min.

Example 692-(4-cyclobutyl-1H-imidazol-1-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 399.2 (M+H⁺); UPLC rt 0.85 min.

Example 702-(4-cyclobutyl-1H-imidazol-1-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 418.2 (M+H⁺); UPLC rt 0.94 min.

Example 712-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-iodo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.71-1

To a stirred solution of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(1.78 g, 5.03 mmol) in 1,2-dichloroethane (50 mL) was added POCl₃ (0.94mL, 10.1 mmol) and the resulting suspension was stirred at 100° C. for 1h. The reaction mixture was cooled to rt and concentrated under reducedpressure to dryness. For complete removal of POCl₃ the residue was takenup in toluene and evaporated twice again and dried under high vacuo.

The resulting crude chloro compound was dissolved in 1,2-dichloroethane(50 mL), 4-(methoxymethyl)-1H-imidazole (2.24 g, 20.0 mmol) was addedand the mixture was stirred at 100° C. for 2 h. The reaction mixture wasallowed to warm to rt and diluted with DCM.

Saturated aqueous NaHCO₃ solution was added and the mixture wasextracted twice with DCM. The combined organic layers were dried withsodium sulfate, filtered and the solvent was removed under reducedpressure. The crude product was purified by flash-column chromatographyover silicagel (Biotage Isolera Four, eluent: AcOEt/DCM 9:1 isocraticfor 10 min, then from 1% MeOH in DCM to 2.5% MeOH in DCM in 12 min) toyield 1.44 g of a redbrown foam. Further purification by SFC (column:PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: isocratic 5% MeOH/CO₂ for23 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound(739 mg). UPLC-MS: MS 403.2 (M+H⁺); UPLC rt 0.98 min.

Step 2:2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 71

To a degassed solution of9-iodo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(191 mg, 0.43 mmol) and 2-(tributylstannyl)thiazole (239 mg, 0.64 mmol)in dioxane (4 mL) was added Pd(PPh₃)₄ (25 mg, 0.021 mmol) and themixture was heated in the microwave at 150° C. for 2 h. The solvent wasremoved under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: from 1% MeOH in DCM to 5% MeOH in DCM in 18 min) to yield thetitle compound (64 mg). UPLC-MS: MS 406.1 (M+H⁺); UPLC rt 0.81 min. ¹HNMR (600 MHz, DMSO-d₆): 8 ppm 3.18-3.31 (m, 5H), 3.78 (t, J=6.0 Hz, 2H),4.30 (s, 4H), 7.18 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.86(d, J=7.7 Hz, 1H), 7.93 (d, J=3.3 Hz, 1H), 8.04 (d, J=3.3 Hz, 1H), 8.13(d, J=8.1 Hz, 1H), 8.24 (s, 1H).

Following the procedure described above for Example 71 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 722-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 401.4 (M+H⁺); UPLC rt 0.82 min.

Example 732-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-imidazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 401.3 (M+H⁺); UPLC rt 0.55 min.

Example 742-(4-ethyl-1H-imidazol-1-yl)-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 374.1 (M+H⁺); UPLC rt 0.75 min.

Example 752-(4-ethyl-1H-imidazol-1-yl)-9-(furan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 373.2 (M+H⁺); UPLC rt 0.92 min.

Example 762-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 420.2 (M+H⁺); UPLC rt 0.75 min.

Example 772-(4-methoxymethyl)-1H-imidazol-1-yl)-9-(5-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 420.2 (M+H⁺); UPLC rt 0.92 min.

Example 782-(4-methyl-1H-imidazol-1-yl)-9-(pyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 371.2 (M+H⁺); UPLC rt 0.61 min.

Example 792-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 370.2 (M+H⁺); UPLC rt 0.64 min.

Example 802-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 370.2 (M+H⁺); UPLC rt 0.60 min.

Example 819-(6-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 388.2 (M+H⁺); UPLC rt 0.76 min.

Example 822-(4-methyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 376.2 (M+H⁺); UPLC rt 0.70 min.

Example 832-(4-chloro-1H-imidazol-1-yl)-9-(5-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 408.3 (M+H⁺); UPLC rt 0.94 min.

Example 849-(6-fluoropyridin-3-yl)-2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 432.3 (M+H⁺); UPLC rt 0.83 min.

Example 852-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-vinyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 349.2 (M+H⁺); UPLC rt 0.86 min.

Example 862-(4-ethyl-1H-imidazol-1-yl)-9-(4-fluorophenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 401.2 (M+H⁺); UPLC rt 1.03 min.

Example 872-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 400.2 (M+H⁺); UPLC rt 0.95 min.

Example 882-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 400.2 (M+H⁺); UPLC rt 0.94 min.

Example 88a2-(4-(oxazol-2-yl)-1H-imidazol-1-yl)-9-propyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 388.1 (M+H⁺); UPLC rt 1.00 min.

Starting from bromo-[O]-intermediate, instead of iodo-[O]-intermediate

Example 88b2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 416.2 (M+H⁺); UPLC rt 0.96 min.

Example 88c2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 0.98 min.

Example 88d2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 402.1 (M+H⁺); UPLC rt 0.89 min.

Example 88e2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methylthiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 416.1 (M+H⁺); UPLC rt 0.96 min.

Example 88f (from Precursor Described in Preparation 17)2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 397.3 (M+H⁺); UPLC rt 0.79 min.

Example 88g (from Precursor Described in Preparation 17)2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 403.3 (M+H⁺); UPLC rt 1.01 min.

Example 88h (from Precursor Described in Preparation 17)2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 420.2 (M+H⁺); UPLC rt 0.83 min.

Example 88i (from Precursor Described in Preparation 17)2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(4-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 434.2 (M+H⁺); UPLC rt 0.98 min.

Example 88j (from Precursor Described in Preparation 17)2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 420.2 (M+H⁺); UPLC rt 0.88 min.

Example 88k (from Precursor Described in Preparation 17)2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 414.3 (M+H⁺); UPLC rt 0.83 min.

Example 899-ethyl-2-(4-isopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

To a degassed solution of9-iodo-2-(4-isopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(20 mg, 0.045 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (2 mg, 2.24 μmol) indioxane (1 mL) was added diethylzinc (135 μL, 0.135 mmol, 1M in hexane)and the mixture was heated in the microwave at 80° C. for 44 h. Thereaction mixture was allowed to warm to rt and then diluted with AcOEtand 2M aqueous HCl. The organic phase was separated, dried over sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent:7% MeOH/CO₂ for 1 min, then from 7% MeOH/CO₂ to 12% MeOH/CO₂ in 6 min;flow 100 mL/min; UV detection at 220 nm) to yield the title compound (5mg). UPLC-MS: MS 349.2 (M+H⁺); UPLC rt 1.01 min. ¹H NMR (400 MHz,CHLOROFORM-d): δ ppm 1.21-1.28 (m, 9H) 2.72 (q, J=7.4 Hz, 2H) 2.85-2.92(m, 1H) 2.96 (t, J=6.2 Hz, 2H) 3.91 (t, J=6.3 Hz, 2H) 4.35 (br. s., 2H)6.61 (s, 1H) 7.18 (s, 1H) 7.27-7.38 (m, 2H) 7.52 (d, J=7.3 Hz, 1H) 7.93(s, 1H).

Example 902-(4-methyl-1H-imidazol-1-yl)-9-propyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-propyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.90-1

To a degassed solution of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(1.0 g, 2.82 mmol) and propylzinc(II)-bromide (14.1 mL, 7.05 mmol, 0.5Min THF) in dioxane (28 mL) was added PEPPSI-iPr (0.29 g, 0.424 mmol)under argon and the mixture was heated in a pressure vessel at 120° C.for 2.5 h. The reaction mixture was allowed to warm to rt and thesolvent was removed under reduced pressure. The residue was suspended inDCM/MeOH (9:1, v/v), filtrated through a pad of celite and the filtratewas evaporated under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: from 1% MeOH in DCM to 10% MeOH in DCM in 35 min) to yield theproduct as an oil. The title compound was crystallized from diethylether to afford yellow crystals (370 mg). UPLC-MS: MS 271.2 (M+H⁺); UPLCrt 0.86 min.

Step 2:2-(4-methyl-1H-imidazol-1-yl)-9-propyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 90

To a stirred solution of9-propyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(370 mg, 1.36 mmol) in 1,2-dichloroethane (14 mL) was added POCl₃ (0.25mL, 2.73 mmol) and the resulting suspension was stirred at 100° C. for 1h. The reaction mixture was cooled to RT and concentrated under reducedpressure to dryness. For complete removal of POCl₃ the residue was takenup in toluene and evaporated twice again and dried under high vacuo.

The resulting crude chloro compound was dissolved in 1,2-dichloroethane(14 mL), 4-methyl-1H-imidazole (335 mg, 4.08 mmol) was added and themixture was stirred at 100° C. for 2 h. The reaction mixture was allowedto warm to RT and diluted with DCM. Saturated aqueous NaHCO₃ solutionwas added and the mixture was extracted twice with DCM. The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 1% MeOH in DCM for 5 min, then to 5% MeOH in DCM in 25 min, then5% MeOH in DCM for 3 min) to yield 153 mg of a red foam. Furtherpurification by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton;eluent: 11% MeOH/CO₂ for 1 min, then from 11% MeOH/CO₂ to 16% MeOH/CO₂in 6 min; flow 100 mL/min; UV detection at 220 nm) gave the titlecompound which was crystallized from diethyl ether (55 mg). UPLC-MS: MS335.2 (M+H⁺); UPLC rt 0.92 min. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.92 (t,J=7.2 Hz, 3H), 1.52 (sxt, J=7.3 Hz, 2H), 2.11 (s, 3H), 2.61 (t, J=7.6Hz, 2H), 2.90 (br. s., 2H), 3.79 (br. s., 2H), 4.21 (br. s., 2H), 7.10(s, 1H), 7.22-7.33 (m, 2H), 7.38 (s, 1H), 7.84 (d, J=7.3 Hz, 1H), 8.11(s, 1H).

Following the procedure described above for Example 90 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 919-cyclobutyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: 377.3 (M+H⁺); UPLC rt 1.01 min.

Example 929-cyclobutyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 348.2 (M+H⁺); UPLC rt 1.08 min.

Example 939-cyclopropyl-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 364.2 (M+H⁺); UPLC rt 0.98 min.

Example 944-(6-fluoropyridin-3-yl)-11-(4-isopropyl-1H-imidazol-1-yl)-5,6-dihydro-[1,4]diazepino[1,7-h][1,7]naphthyridin-8(9H)-one

Step 1: tert-butyl (2-(2-bromo-4-chloropyridin-3-yl)ethyl)carbamate.94-1

To a stirred solution of LDA (5.98 mmol) in THF (50 mL)2-bromo-4-chloropyridine (1.0 g, 5.20 mmol) was added at −70° C. and theresulting solution was stirred at −70° C. for 1 h. Then a solution oftert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.39 g, 6.24mmol) in THF (20 mL) was added at −70° C. and the reaction mixture wasstirred for 3 h. Saturated aqueous NH₄Cl solution was added at −70° C.and the mixture was allowed to warm to RT. The mixture was extractedwith AcOEt (2×). The combined organic layers were washed with brine,dried with sodium sulfate, filtered and the solvent was removed underreduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera One, eluent: gradientfrom 2% MeOH in DCM to 13% MeOH in DCM in 12 min) to yield the titlecompound as a white solid (1.36 g). UPLC-MS: MS 335.1 (M+H⁺); UPLC rt1.06 min.

Step 2: di-tert-butyl(2-(2-bromo-4-chloropyridin-3-yl)ethyl)imidodicarbonate. 94-2

To a stirred solution of tert-butyl(2-(2-bromo-4-chloropyridin-3-yl)ethyl)carbamate (1.15 g, 3.43 mmol) indioxane (50 mL) Boc₂O (3.0 g, 13.7 mmol) and DMAP (42 mg, 0.34 mmol) wasadded and the resulting yellow solution was stirred at reflux for 72 h.The reaction mixture was allowed to warm to rt and saturated aqueousNaHCO₃ solution was added. The mixture was extracted with AcOEt (2×).The combined organic layers were washed with brine, dried with sodiumsulfate, filtered and the solvent was removed under reduced pressure.The crude product was purified by flash-column chromatography oversilicagel (Biotage Isolera One, eluent: gradient from 6% AcOEt incyclohexane to 40% AcOEt in cyclohexane in 18 min) to yield the titlecompound as a white solid (1.42 g). UPLC-MS: MS 435.1 (M+H⁺); UPLC rt1.36 min.

Step 3: (E)-methyl3-(3-(2-((di-tert-butoxycarbonyl)amino)ethyl)-4-chloropyridin-2-yl)acrylate.94-3

A mixture of 94-2 (700 mg, 1.61 mmol), methyl acrylate (290 mg, 3.37mmol), bis(tri-tert-butylphosphine)palladium(0) (25 mg, 0.048 mmol) andN,N-dicyclohexyl-methylamine (690 mg, 3.53 mmol) in dioxane (10 mL) wasstirred under Argon at 150° C. for 2 h in the microwave. The solvent wasremoved under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera One, eluent:gradient from 7% AcOEt in cyclohexane to 100% AcOEt in cyclohexane in 18min) to yield the title compound as a clear oil (520 mg). UPLC-MS: MS441.2 (M+H⁺); UPLC rt 1.37 min.

Step 4: (E)-methyl 3-(3-(2-aminoethyl)-4-chloropyridin-2-yl)acrylate.94-4

To a stirred solution of 94-3 (520 mg, 1.18 mmol) in DCM (10 mL), TFA(0.91 mL, 11.79 mmol) was added and the reaction mixture was stirred atRT for 64 h. The reaction mixture was evaporated under reduced pressureand the residue was suspended in diethyl ether. The white precipitatewas filtered off and washed with a small amount of diethyl ether (2×).The HCl salt was dried under high vacuo overnight to yield the titlecompound as white solid (380 mg). UPLC-MS: MS 241.1 (M+H⁺); UPLC rt 0.50min.

Step 5: methyl2-(4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate. 94-5

A yellow solution of (E)-methyl3-(3-(2-aminoethyl)-4-chloropyridin-2-yl)acrylate (530 mg, 1.49 mmol)and triethylamine (1.04 mL, 7.47 mmol) in dioxane (10 mL) was stirred at50° C. for 1 h. The solvent was removed under reduced pressure. Thecrude product was purified by flash-column chromatography over silicagel(Biotage Isolera One, eluent: gradient from 2% MeOH in DCM to 20% MeOHin DCM in 14 min) to yield the title compound as a clear oil (308 mg).UPLC-MS: MS 241.1 (M+H⁺); UPLC rt 0.43 min.

Step 6: methyl2-(7-(2-((tert-butoxycarbonyl)amino)acetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate.94-6

To a stirred solution of methyl2-(4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate (320 mg,1.33 mmol), Boc-glycine (233 mg, 1.33 mmol) and triethylamine (0.37 mL,2.66 mmol) in AcOEt (7 mL), T3P (0.93 mL, 1.59 mmol, 50% m/m in DMF) wasadded and the solution was stirred at RT for 16 h. Water was added andthe mixture was extracted with AcOEt (2×). The combined organic layerswere dried with sodium sulfate, filtered and the solvent was removedunder reduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera One, eluent: gradientfrom 0% AcOEt in cyclohexane to 100% AcOEt in cyclohexane in 21 min) toyield the title compound as a clear oil (510 mg). UPLC-MS: MS 398.1(M+H⁺); UPLC rt 0.95 min.

Step 7: sodium2-(7-(2-((tert-butoxycarbonyl)amino)acetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate.94-7

To a stirred solution of methyl2-(7-(2-((tert-butoxycarbonyl)amino)acetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate(540 mg, 1.36 mmol) in MeOH (10 mL), 4N aqueous NaOH (0.39 mL, 1.56mmol) was added and the solution was stirred at RT for 5 days. Thesolvent was evaporated under reduced pressure. The residue was driedunder high vacuo overnight to yield the title compound as a beige powder(540 mg) which was used without further purification in the next step.UPLC-MS: MS 384.1 (M+H⁺); UPLC rt 0.81 min.

Step 8:2-(8-(carboxymethyl)-4-chloro-5,6-dihydro-1,7-naphthyridin-7(8H)-yl)-2-oxoethanaminiumchloride. 94-8

To a stirred suspension of sodium2-(7-(2-((tert-butoxycarbonyl)amino)acetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetate(540 mg, 1.41 mmol) in dioxane (10 mL), 4N HCl in dioxane (1.76 mL, 7.03mmol) was added and the reaction mixture was stirred at RT for 48 h. Thebeige precipitate was filtered off washed with a small amount of diethylether (2×). The HCl salt was dried under high vacuo overnight to yieldthe title compound as beige solid (590 mg) containing a residual amountof NaCl. UPLC-MS: MS 284.1 (M+H⁺); UPLC rt 0.45 min.

Step 9:4-chloro-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione.94-9

To a stirred solution of2-(7-(2-aminoacetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)aceticacid (HCl-salt) (450 mg, 1.41 mmol) and triethylamine (1.17 mL, 8.43mmol) in DCM (20 mL), T3P (1.25 mL, 2.11 mmol, 50% m/m in AcOEt) wasadded slowly and the suspension was stirred at RT for 1 h. Saturatedaqueous NaHCO₃ solution was added and the mixture was extracted with DCM(2×). The combined organic layers were dried with sodium sulfate,filtered and the solvent was removed under reduced pressure. The crudeproduct was purified by flash-column chromatography over silicagel(Biotage Isolera One, eluent: gradient from 2% MeOH in AcOEt to 15% MeOHin AcOEt in 18 min) to yield the title compound as a beige solid (66mg). UPLC-MS: MS 266.1 (M+H⁺); UPLC rt 0.57 min.

Step 10:4-(6-fluoropyridin-3-yl)-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione.94-10

To a degassed solution of4-chloro-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione(66 mg, 0.25 mmol) and 2-fluoro-5-(tributylstannyl)pyridine (120 mg,0.31 mmol) in dioxane (2 mL) Pd(PPh₃)₄ (15 mg, 0.012 mmol) was added andthe mixture was heated in the microwave at 150° C. for 5 h. The solventwas removed under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: from 2% MeOH in AcOEt to 20% MeOH in AcOEt in 21 min) to yieldthe title compound as a beige solid (32 mg). UPLC-MS: MS 327.2 (M+H⁺);UPLC rt 0.58 min.

Step 11:4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione.94-11

A mixture of4-(6-fluoropyridin-3-yl)-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione(32 mg, 0.098 mmol) and SeO₂ (19 mg, 0.17 mmol) in pyridine (1.5 mL) wasstirred at 160° C. for 30 min under microwave conditions. The reactionmixture was allowed to warm to rt and poured into saturated aqueousNaHCO₃ solution. The mixture was extracted with AcOEt (3×). The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The crude product was dried underhigh vacuo overnight to yield the title compound as a beige solid (32mg) which was used without further purification in the next step.UPLC-MS: MS 325.2 (M+H⁺); UPLC rt 0.65 min.

Step 12:4-(6-fluoropyridin-3-yl)-11-(4-isopropyl-1H-imidazol-1-yl)-5,6-dihydro-[1,4]diazepino[1,7-h][1,7]naphthyridin-8(9H)-one.Example 94

To a stirred solution of4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione(31 mg, 0.096 mmol) in 1,2-dichloroethane (2 mL) POCl₃ (29.3 mg, 0.19mmol) was added and the resulting suspension was stirred at 100° C. for1 h. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and evaporated twice again and dried under highvacuo. The resulting crude chloro compound was dissolved in1,2-dichloroethane (5 mL), 4-isopropyl-1H-imidazole (53 mg, 0.48 mmol)was added and the mixture was stirred at 100° C. for 1 h. The reactionmixture was allowed to warm to rt and diluted with DCM. Saturatedaqueous NaHCO₃ solution was added and the mixture was extracted twicewith DCM. The combined organic layers were dried with sodium sulfate,filtered and the solvent was removed under reduced pressure. The crudeproduct was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60 A,Princeton; eluent: from 6% MeOH/CO₂ to 11% MeOH/CO₂ in 11 min; flow 100mL/min; UV detection at 220 nm) and yielded the title compound as beigepowder (11 mg). UPLC-MS: MS 417.2 (M+H⁺); UPLC rt 0.87 min. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 6H), 2.81-2.98 (m, 3H), 4.05 (br.s., 2H), 4.40 (s, 2H), 7.09 (dd, J=8.3, 2.8 Hz, 1H), 7.22-7.36 (m, 2H),7.77 (td, J=7.9, 2.1 Hz, 1H), 7.96 (s, 1H), 8.03 (s, 1H), 8.23 (d, J=1.5Hz, 1H), 8.68 (d, J=4.8 Hz, 1H).

Example 95-12-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.95-1-1

To a stirred solution of9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(2.0 g, 6.51 mmol) in 1,2-dichloroethane (65 mL) was added POCl₃ (1.21mL, 13.02 mmol) at RT and the resulting suspension was stirred at 100°C. for 1 h. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and the solvent was evaporated under reducedpressure. The residue was dried under high vacuo at RT.

The resulting crude chloro intermediate was dissolved in1,2-dichloroethane (50 mL), a solution of 4-cyclopropyl-1H-imidazole(2.11 g, 19.53 mmol) in 1,2-dichloroethane (15 mL) was added and themixture was stirred at 100° C. for 2 h. The reaction mixture was allowedto warm to rt and diluted with DCM. Saturated aqueous NaHCO₃ solutionwas added and the mixture was extracted twice with DCM. The combinedorganic layers were washed with brine, dried with sodium sulfate,filtered and the solvent was removed under reduced pressure. The crudeproduct was purified by flash-column chromatography over silicagel(Biotage Isolera Four, eluent: 1% MeOH in DCM for 5 min, then from 1%MeOH in DCM to 4% MeOH in DCM in 25 min, 4% MeOH in DCM for 5 min) toyield 1.72 g of a redbrown foam. A second flash-column chromatographyover silicagel was done (Biotage Isolera Four, eluent: 20% AcOEt in DCMfor 3 min, then from 20% AcOEt in DCM to 80% AcOEt in DCM in 25 min,followed by 80% AcOEt in DCM for 10 min) to yield the title compound asa yellow solid (1.48 g). UPLC-MS: MS 397.1/399.1 (M+H⁺); UPLC rt 1.00min.

Step 2:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 95-1

9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(1.48 g, 3.73 mmol), (6-fluoropyridin-3-yl)boronic acid (1.05 g, 7.45mmol) and a solution of Na₂CO₃ (1.97 g, 18.63 mmol) in water (14.5 mL)was treated with DME (58 mL). The suspension was degassed, Pd(PPh₃)₄(646 mg, 0.56 mmol) was added and the mixture was heated at 85° C. for 2h. The mixture was allowed to warm to RT and the solvent was removedunder reduced pressure. The residue was dissolved in DCM and extractedwith water, saturated aqueous NaHCO₃ solution and brine. The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 4% MeOH inDCM in 25 min, 4% MeOH in DCM for 5 min) to yield a beige foam (1.04 g).The residue was crystallized from AcOEt to afford the title compound aswhite crystals (720 mg). UPLC-MS: MS 414.2 (M+H⁺); UPLC rt 0.95 min. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.66 (d, J=3.4 Hz, 2H), 0.72-0.84 (m, 2H),1.70-1.88 (m, 1H), 2.84 (br. s., 2H), 3.72 (br. s., 2H), 4.24 (br. s.,2H), 7.18 (s, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.47-7.57 (m,2H), 7.97-8.14 (m, 3H), 8.27 (s, 1H).

Example 95-22-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.95-2-1

To a stirred solution of9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(5.0 g, 16.28 mmol) in 1,2-dichloroethane (203 mL) was added POCl₃ (3.03mL, 32.6 mmol) at rt and the resulting suspension was stirred at 100° C.for 35 min. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and the solvent was evaporated under reducedpressure. The residue was dried under high vacuo at rt.

The resulting crude chloro intermediate was dissolved in1,2-dichloroethane (190 mL), a solution of3-cyclopropyl-1H-1,2,4-triazole (2.66 g, 24.37 mmol) in1,2-dichloroethane (15 mL) was added and the mixture was stirred at 100°C. for 2 h. The reaction mixture was allowed to warm to rt and dilutedwith DCM. Saturated aqueous NaHCO₃ solution was added and the mixturewas extracted twice with DCM. The combined organic layers were washedwith brine, dried with sodium sulfate, filtered and the solvent wasremoved under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 0.5% MeOH in DCM for 3 min, then from 0.5% MeOH in DCM to 2.5%MeOH in DCM in 50 min, 2.5% MeOH in DCM for 5 min) to yield slightly redfoam. The residue was triturated with AcOEt to yield the title compoundas a slightly red solid (3.92 g). UPLC-MS: MS 398.2/400.2 (M+H⁺); UPLCrt 1.08 min.

Step 2:2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 95-2

9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(5.7 g, 14.31 mmol), (6-fluoropyridin-3-yl)boronic acid (4.03 g, 28.6mmol) and a solution of Na₂CO₃ (7.58 g, 71.6 mmol) in water (28 mL) wastreated with DME (114 mL). The suspension was degassed, Pd(PPh₃)₄ (2.48g, 2.15 mmol) was added and the mixture was heated at 85° C. for 2 h.The mixture was allowed to warm to RT and the solvent was removed underreduced pressure. The residue was dissolved in DCM and extracted withwater, saturated aqueous NaHCO₃ solution and brine. The combined organiclayers were dried with sodium sulfate, filtered and the solvent wasremoved under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 70% AcOEt in heptane for 3 min, then from 70% AcOEt in heptaneto 100% AcOEt in heptane in 50 min, 100% AcOEt in heptane for 10 min) toyield a beige foam (5.91 g). The residue was dissolved in DCM (100 mL)and MP-TMT resin (4.0 g, 0.71 mmol/g) was added and the mixture wasstirred for 2.5 h. The resin was filtered off and the solvent wasremoved under reduced pressure to yield a yellow foam. The foam wascrystallized from hot n-butanol (50 mL) to afford the title compound aswhite crystals (4.8 g). UPLC-MS: MS 415.4 (M+H⁺); UPLC rt 1.02 min. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.87 (m, 2H), 0.89-0.99 (m, 2H),1.98-2.07 (m, 1H), 2.87 (t, J=6.11 Hz, 2H), 3.72 (t, J=6.11 Hz, 2H),4.30 (s, 2H), 7.05 (s, 1H), 7.31 (dd, J=8.44, 2.57 Hz, 1H), 7.47-7.56(m, 2H), 7.89-7.97 (m, 1H), 8.07 (td, J=8.13, 2.57 Hz, 1H), 8.30 (d,J=2.45 Hz, 1H), 9.00 (s, 1H).

Example 96-19-cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.96-1-1

To a stirred solution of9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(10.0 g, 32.6 mmol) in 1,2-dichloroethane (500 mL) was added POCl₃ (6.07mL, 65.1 mmol) at RT and the resulting suspension was stirred at 100° C.for 1 h. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and the solvent was evaporated under reducedpressure. The residue was dried under high vacuo at RT.

The resulting crude chloro intermediate (14.85 g) was dissolved in1,2-dichloroethane (400 mL), a solution of4-(methoxymethyl)-1H-imidazole (10.97 g, 98 mmol) in 1,2-dichloroethane(100 mL) was added and the mixture was stirred at 100° C. for 2 h. Thereaction mixture was allowed to warm to RT and diluted with DCM.Saturated aqueous NaHCO₃ solution was added and the mixture wasextracted twice with DCM. The combined organic layers were washed withbrine, dried with sodium sulfate, filtered and the solvent was removedunder reduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera Four, eluent: AcOEt/DCM9:1 for 20 min, then from 1% MeOH in DCM to 2.5% MeOH in DCM in 25 min,2.5% MeOH in DCM for 35 min) to yield 8.35 g of a redbrown foam. Theresidue was dissolved in AcOEt (50 mL) and stirred overnight while thedesired regioisomer crystallized. The solid was filtered of, washed witha small amount of AcOEt and dried overnight under high vacuo to yieldthe title compound as pale yellow crystals (2.6 g). UPLC-MS: MS401.2/403.2 (M+H⁺); UPLC rt 0.91 min.

Step 2:9-cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 96-1

9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(7.73 g, 19.26 mmol) was dissolved in toluene (155 mL) and S-Phos (2.58g, 6.16 mmol), cyclopropylboronic acid (3.45 g, 38.5 mmol) and K₃PO₄(8.59 g, 40.5 mmol) were added. The suspension was degassed, Pd(OAc)₂(0.87 g, 3.85 mmol) was added under Argon and the mixture was heated at100° C. for 1 h. The mixture was allowed to warm to RT and filteredthrough a pad of celite. The residue was diluted with DCM and extractedwith water, saturated aqueous NaHCO₃ solution and brine. The combinedorganic layers were dried with sodium sulfate, filtered and the solventwas removed under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 1% MeOH in DCM for 5 min, then from 1% MeOH in DCM to 5% MeOH inDCM in 60 min, 5% MeOH in DCM for 10 min) to yield a beige foam (6.85g). The residue was crystallized from AcOEt to afford the title compoundas white crystals (5.8 g). UPLC-MS: MS 363.3 (M+H⁺); UPLC rt 0.95 min.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.50-0.72 (m, 2H), 0.79-1.06 (m, 2H),1.77-2.08 (m, 1H), 2.93-3.14 (m, 2H), 3.24 (s, 3H), 3.87 (br. s, 2H),4.13-4.39 (m, 4H), 7.09-7.21 (m, 2H), 7.24-7.35 (m, 1H), 7.62 (s, 1H),7.84-7.94 (m, 1H), 8.20 (s, 1H).

Example 96-29-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-bromo-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.96-2-1

To a stirred solution of9-bromo-10-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(see preparation 17a) (4.40 g, 13.53 mmol) in 1,2-dichloroethane (135mL) was added POCl₃ (2.52 mL, 27.1 mmol) at RT and the resultingsuspension was stirred at 100° C. for 30 min. The reaction mixture wascooled to rt and concentrated under reduced pressure to dryness. Forcomplete removal of POCl₃ the residue was taken up in toluene and thesolvent was evaporated under reduced pressure. The residue was driedunder high vacuo at RT.

The resulting crude chloro intermediate (4.65 g) was dissolved in1,2-dichloroethane (135 mL), 4-(methoxymethyl)-1H-imidazole (6.07 g,54.1 mmol) was added and the mixture was stirred at 100° C. for 1.5 h.The reaction mixture was allowed to warm to RT and diluted with DCM.Water was added and the mixture was extracted twice with DCM. Thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered and the solvent was removed under reduced pressure.The crude product was purified by flash-column chromatography oversilicagel (Biotage Isolera Four, eluent: 0.5% MeOH in DCM for 5 min,then from 0.5% MeOH in DCM to 4% MeOH in DCM in 50 min, 4% MeOH in DCMfor 10 min) to yield a beige foam. The residue was triturated with AcOEtto yield beige crystals. For a complete regioisomer separation thecrystals were once again crystallized from AcOEt (25 mL) and stirredovernight. The solid was filtered of, washed with a small amount ofAcOEt and dried overnight under high vacuo to yield the title compoundas pale yellow crystals (1.5 g). UPLC-MS: MS 419.2/421.2 (M+H)⁺; UPLC rt3.22 min (10 min method).

Step 2:9-cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 96-2

9-bromo-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(1.5 g, 3.58 mmol) was dissolved in toluene (36 mL) and S-Phos (0.47 g,1.14 mmol), cyclopropylboronic acid (0.615 g, 7.16 mmol) and K₃PO₄ (1.59g, 7.51 mmol) were added. The suspension was degassed, Pd(OAc)₂ (0.16 g,0.72 mmol) was added under Argon and the mixture was heated at 100° C.for 1.5 h. The mixture was allowed to warm to RT and filtered through apad of celite. The residue was diluted with DCM and extracted withwater, saturated aqueous NaHCO₃ solution and brine. The combined organiclayers were dried with sodium sulfate, filtered and the solvent wasremoved under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: 50% AcOEt in DCM for 5 min, then from 50% AcOEt in DCM to 100%AcOEt in DCM in 40 min, followed by 100% AcOEt in DCM for 10 min)) toyield a foam. A second flash-column chromatography over silicagel wasdone (Biotage Isolera Four, eluent: 0.5% MeOH in DCM for 4 min, thenfrom 0.5% MeOH in DCM to 4% MeOH in DCM in 60 min, 4% MeOH in DCM for20) to yield the title compound as a yellow solid. The residue wasdissolved in DCM and MP-TMT resin (0.71 mmol/g) was added and themixture was stirred for 2.5 h. The resin was filtered off and thesolvent was removed under reduced pressure to yield a yellow foam. Thefoam was crystallized from hot n-butanol to afford the title compound aswhite crystals (683 mg). UPLC-MS: MS 381.3 (M+H⁺); UPLC rt 3.53 min (10min method). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.55-0.64 (m, 2H),0.94-1.04 (m, 2H), 1.67-1.78 (m, 1H), 3.08 (t, J=5.99 Hz, 2H), 3.23 (s,3H), 3.77-3.88 (m, 2H), 4.22 (br. s., 2H), 4.27 (s, 2H), 7.10-7.20 (m,2H), 7.63 (s, 1H), 7.98 (dd, J=8.93, 5.01 Hz, 1H), 8.20 (d, J=1.47 Hz,1H).

Following the procedure described above for Example 95-1, 95-2, 96-1 and96-2, and substituting the appropriate reagents, starting materials andpurification methods known to those skilled in the art, the followingcompounds of the present invention were prepared:

Example 972-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 414.2 (M+H⁺); 0.89 min.

Example 982-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 428.2 (M+H⁺); UPLC rt 0.96 min.

Example 992-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2,6-difluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 432.2 (M+H⁺); UPLC rt 1.01 min.

Example 99a2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 374.1 (M+H⁺); UPLC rt 0.73 min.

Example 99b2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 453.3 (M+H⁺); UPLC rt 0.98 min.

Example 99c2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-hydroxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 412.4 (M+H⁺); UPLC rt 0.71 min.

Example 99d2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-methoxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 426.4 (M+H⁺); UPLC rt 1.01 min.

Example 99e2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 385.4 (M+H⁺); UPLC rt 0.78 min.

Example 99f2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.3 (M+H⁺); UPLC rt 0.87 min.

Example 99g2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 414.2 (M+H⁺); UPLC rt 0.94 min.

Example 99h2-(3-cyclobutyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 429.3 (M+H⁺); UPLC rt 1.11 min.

Example 99i (from Precursor Described in Preparation 17b)9-cyclopropyl-12-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 381.3 (M+H⁺); UPLC rt 0.96 min.

Example 99j (from Precursor Described in Preparation 17b)(R)-9-cyclopropyl-12-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 395.3 (M+H⁺); UPLC rt 1.00 min.

Example 99k (from Precursor Described in Preparation 17c)9-cyclopropyl-11-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 381.2 (M+H⁺); UPLC rt 0.97 min.

Example 99l (from Precursor Described in Preparation 17)9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 369.2 (M+H⁺); UPLC rt 1.05 min.

Example 99m (from Precursor Described in Preparation 17)9-cyclopropyl-2-(4-(fluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 351.2 (M+H⁺); UPLC rt 1.00 min.

Example 99n (from Precursor Described in Preparation 17a)(R)-9-cyclopropyl-10-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 395.4 (M+H⁺); UPLC rt 1.00 min.

Example 99o (from Precursor Described in Preparation 17a)10-fluoro-9-(6-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 407.3 (M+H⁺); UPLC rt 0.92 min.

Example 99p (from Precursor Described in Preparation 17a)9-cyclopropyl-10-fluoro-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 382.3 (M+H⁺); UPLC rt 1.01 min.

Example 99q (from Precursor Described in Preparation 17a)2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-10-fluoro-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 433.3 (M+H⁺); UPLC rt 1.00 min.

Example 99r (from Precursor Described in Preparation 17a)10-fluoro-9-(2-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 407.3 (M+H⁺); UPLC rt 0.89 min.

Example 99s (from Precursor Described in Preparation 17a)10-fluoro-9-(2-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 406.3 (M+H⁺); UPLC rt 0.78 min.

Example 1002-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.100-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(150 mg, 0.42 mmol), tributyl(1-ethoxyvinyl)stannane (153 mg, 0.42 mmol)and Pd(PPh₃)₄ (49 mg, 0.04 mmol) in dioxane (3 mL) was heated to 140° C.for 2 h in a microwave reactor. The mixture was then concentrated invacuo and the residue obtained was purified by flash chromatography(SiO₂, heptane to AcOEt to AcOEt/MeOH 85:15) afforded the compoundobtained was taken up in THF (20 mL) and treated with a 2M aqueoussolution of HCl (0.68 mL, 1.36 mmol). The solution was stirred at RT for1 h and then concentrated in vacuo. The residue obtained was taken up ina saturated aq. solution of NaHCO₃ and extracted with DCM. The combinedorg. layers were then dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (79 mg). UPLC-MS: MS 271.2 (M+H⁺); UPLCrt 0.59 min.

Step 2:(E)-9-(3-(dimethylamino)acryloyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.100-2

A mixture of9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(200 mg, 0.74 mmol) in DMF (1.0 mL) was treated with DMF-DMA (0.12 mL,0.89 mmol) and stirred at 100° C. for 1 h. The mixture was concentratedin vacuo and the crude product obtained was purified by flashchromatography (SiO₂, DCM/MeOH 98:2 to 85:15) to give the title compound(135 mg) as a beige solid. UPLC-MS: MS 236.2 (M+H⁺), UPLC rt 0.54 min.

Step 3:9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.100-3

NH₂OH*HCl (51 mg, 0.74 mmol) was added to a mixture of(E)-9-(3-(dimethylamino)acryloyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(160 mg, 0.49 mmol) in MeOH (5 mL) and the solution was heated to refluxfor 1 h. The mixture was then concentrated in vacuo and the crudeproduct was purified by flash chromatography (SiO₂, DCM/MeOH 99:1 to90:10) to afford the title compound (90 mg) as a beige solid. UPLC-MS:MS 296.1 (M+H⁺). UPLC rt 0.65 nm.

Step 4:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 100

A solution of9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl₃ (57 μL, 0.61mmol) and the mixture was heated to 100° C. for 1 h. The mixture wasthen allowed to cool to RT, poured onto H₂O and extracted with DCM. Theorg. phases were then dried over Na₂SO₄, filtered and concentrated invacuo. The brown residue obtained was taken up in DCE (4 mL) and4-cyclopropyl-1H-imidazole (50 mg, 0.46 mmol) and pyridine (74 μL, 0.91mmol) were then added. The mixture was heated to 110° C. for 1 h, andthen allowed to cool to RT, poured onto H₂O and extracted with DCM. Theorg. layers were then dried over Na₂SO₄, filtered and concentrated invacuo. Purification by flash chromatography (SiO₂, cHex/AcOEt 100:0 to0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) asa pale red solid. UPLC-MS: MS 386.2 (M+H⁺); UPLC rt 0.85 min. ¹H NMR(400 MHz, CHLOROFORM-d): δ ppm 0.67-0.79 (m, 2H); 0.80-0.91 (m, 2H);1.80-1.91 (m, 1H); 3.17 (t, J=6.06 Hz, 2H); 3.90 (t, J=6.19 Hz, 2H);4.37 (s, 2H); 6.47 (s, 1H); 6.63 (s, 1H); 7.18 (s, 1H); 7.50 (t, J=7.83Hz, 1H); 7.70-7.83 (m, 2H); 7.88 (s, 1H); 8.38 (s, 1H).

Example 1012-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(thiazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.104-1

To a degassed solution of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1g, 2.82 mmol) and 4-(tributylstannyl)thiazole (1.48 g, 3.95 mmol) indioxane (16 mL) was added Pd(PPh₃)₄ (130 mg, 0.11 mmol) and the mixturewas heated in the microwave at 150° C. for 2 h. The solvent was removedunder reduced pressure. The crude product was crystallized from DCM toyield the title compound (760 mg). UPLC-MS: MS 312.1 (M+H⁺); UPLC rt0.66 min.

Step 2:2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 101

To a stirred solution of9-(thiazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(160 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) POCl₃ (0.096 mL, 1.03mmol) was added and the resulting suspension was stirred at 100° C. for1 h. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and evaporated twice again and dried under highvacuo. The resulting crude chloro compound was dissolved in1,2-dichloroethane (4 mL), 4-(methoxymethyl)-1H-imidazole (172 mg, 1.53mmol) was added and the mixture was stirred at 100° C. for 2 h. Thereaction mixture was allowed to warm to rt and diluted with DCM.Saturated aqueous NaHCO₃ solution was added and the mixture wasextracted twice with DCM. The combined organic layers were dried withsodium sulfate, filtered and the solvent was removed under reducedpressure. The crude product was purified by SFC (column: Reprosil 70NH2, 5 μm, 250×30 mm, Dr. Maisch; eluent: 14% MeOH/CO₂ for 1 min, thenfrom 14% MeOH/CO₂ to 19% MeOH/CO₂ in 6 min; flow 100 mL/min; UVdetection at 220 nm) to yield the title compound as white powder (27mg). UPLC-MS: MS 406.2 (M+H⁺); UPLC rt 0.78 min. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 3.14 (t, J=5.9 Hz, 2H), 3.42 (s, 3H), 3.85 (t, J=6.1Hz, 2H), 4.39 (br. s., 2H), 4.44 (s, 2H), 6.61 (s, 1H), 7.37-7.50 (m,3H), 7.68 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 8.95(s, 1H).

Following the procedure described above for Example 101 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1022-(3-ethyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 403.1 (M+H⁺); UPLC rt 0.96 min.

Example 1032-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-methylisothiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 416.1 (M+H⁺); UPLC rt 0.95 min.

Example 1042-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 386.2 (M+H⁺); UPLC rt 0.87 min.

Example 1052-(4-ethynyl-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 386.2 (M+H⁺); UPLC rt 0.88 min.

Example 1069-(2-fluoropyridin-3-yl)-2-(4-(oxazol-2-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 441.1 (M+H⁺); UPLC rt 0.85 min.

Example 106a9-(6-fluoropyridin-3-yl)-2-(4-(1-methoxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 444.2 (M+H+); UPLC rt 0.96 min.

Example 106b2-(4-methyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 371.2 (M+H+); UPLC rt 0.65 min.

Example 106c (from Precursor Described in Preparation 17)9-(6-fluoropyridin-3-yl)-2-(4-(3-hydroxyoxetan-3-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 446.1 (M+H⁺); UPLC rt 0.80 min.

Example 1072-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.107-1

A mixture of9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(30 mg, 81 μmol) in DCE (2 mL) is treated with POCl₃ (15 μL, 0.16 mmol)and heated to 100° C. for 3 h. The mixture was then allowed to cool toRT, poured onto H₂O and extracted with DCM. The org. phases were driedover Na₂SO₄, filtered and concentrated in vacuo. The brown residueobtained was taken up in DCE (2 mL) and 4-cyclopropyl-1H-imidazole (31mg, 0.28 mmol) and pyridine (20 μL, 0.24 mmol) were then added. Themixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT,poured onto H₂O and extracted with DCM. The org. layers were then driedover Na₂SO₄, filtered and concentrated in vacuo. Filtration through apad of SiO₂ (AcOEt) afforded a brown solid that was purified by SFC(column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent: 13% MeOH/CO₂ for1 min, then from 13% MeOH/CO₂ to 18% MeOH/CO₂ in 6 min; then from 18%MeOH/CO₂ to 50% MeOH/CO₂ in 1 min; flow 100 mL/min; UV detection at 220nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS459.0 (M+H⁺); UPLC rt 0.98 min.

Step 2:2-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 107

A mixture of2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(8 mg, 17 μmol), 3-methyl-5-(tributylstannyl)isoxazole (10 mg, 26 μmol)and Pd(PPh₃)₄ (1.0 mg, 0.9 μmol) in dioxane (0.2 mL) is heated to 140°C. for 1.5 h under N₂ in a microwave reactor. The mixture was thenconcentrated in vacuo the residue obtained was purified by SFC (column:2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 8% MeOH/CO₂for 1 min, then from 8% MeOH/CO₂ to 13% MeOH/CO₂ in 6 min; then from 13%MeOH/CO₂ to 50% MeOH/CO₂ in 1 min; flow 100 mL/min; UV detection at 220nm) to afford the title compound (4 mg) as a beige solid. UPLC-MS: MS414.2 (M+H⁺); UPLC rt 0.88 min. ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm0.74-0.88 (m, 4H); 1.74-1.91 (m, 1H); 2.18 (s, 3H); 2.42 (s, 3H); 2.81(td, J=14.68, 5.27 Hz, 1H); 3.17 (td, J=13.49, 3.64 Hz, 1H); 3.45 (m.,1H); 3.91-4.02 (m, 2H); 4.70 (d, J=10.79 Hz, 1H); 6.32 (s, 1H); 6.95 (s,1H); 7.45 (t, J=7.65 Hz, 1H); 7.56 (d, J=7.78 Hz, 1H); 7.66-7.76 (m,2H).

Example 1082-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(1-ethoxyvinyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.111-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(2.5 g, 7.06 mmol) in dioxane (15 mL) was treated withtributyl(1-ethoxyvinyl)stannane (2.98 mL, 8.82 mmol) and Pd(PPh₃)₄ (408mg, 0.35 mmol) under Ar, and the mixture was heated to 150° C. for 90min in a microwave reactor. The mixture was then filtered and thefiltrate concentrated in vacuo. Purification by flash chromatography(SiO₂, DCM/MeOH 99:1 to 90:10) gave the title compound (1.20 g) as abeige solid. UPLC-MS: MS 299.2 (M+H⁺); UPLC rt 0.85 min.

Step 2:9-(2-bromoacetyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.111-2

A solution of9-(1-ethoxyvinyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(1.2 g, 4.02 mmol) in a mixture of THF/H₂O (3:1, 40 mL) was treated withNBS (716 mg, 4.02 mmol) and the mixture was stirred at 0° C. for 10 min.The mixture was partioned between AcOEt and brine and the org. phase wasseparated, dried over Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (880 mg) that was used as it is in the next step.UPLC-MS: MS 349.0 (M+H⁺); UPLC rt 0.69 min.

Step 3:9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.111-3

A flask was charged with9-(2-bromoacetyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(230 mg, 0.66 mmol) and acetamide (233 mg, 3.95 mmol) and the solidmixture was heated to 130° C. for 15 min. The resulting brown liquidmass was partitioned in AcOEt and H₂O. The org. phase was separated,dried over Na₂SO₄, filtered and concentrated in vacuo. Purification byflash chromatography (SiO₂, AcOEt/MeOH (100:0 to 90:10) gave the titlecompound (110 mg) as a beige powder. UPLC-MS: MS 310.2 (M+H⁺); UPLC rt0.67 min.

Step 4:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 108

A mixture of9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCl₃ (84 μL, 0.91mmol) and heated to 100° C. for 1 h. The mixture was then allowed tocool to RT, poured onto cold H₂O and extracted with DCM. The org. phaseswere dried over Na₂SO₄, filtered and concentrated in vacuo. The brownresidue obtained was taken up in DCE (5 mL) and4-cyclopropyl-1H-imidazole (59 mg, 0.54 mmol) and pyridine (110 μL, 1.36mmol) were then added. The mixture was heated to 100° C. for 1 h, andthen allowed to cool to RT, poured onto H₂O and extracted with DCM. Theorg. layers were then dried over Na₂SO₄, filtered and concentrated invacuo. Purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 10% MeOH/CO₂ for 1 min, then from 10% MeOH/CO₂ to15% MeOH/CO₂ in 6 min; then from 15% MeOH/CO₂ to 50% MeOH/CO₂ in 1 min;flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42mg) as beige powder. UPLC-MS: MS 400.2 (M+H⁺); UPLC rt 0.86 min. 1H NMR(400 MHz, CHLOROFORM-d): δ ppm 0.61-0.82 (m, 2H); 0.82-0.91 (m, 2H);1.78-1.96 (m, 1H); 2.56 (s, 3H); 3.16 (t, J=6.02 Hz, 2H); 3.89 (t,J=6.15 Hz, 2H); 4.37 (br. s., 2H); 6.62 (s, 1H); 7.19 (d, J=1.25 Hz,1H); 7.38-7.48 (m, 1H); 7.63-7.70 (m, 2H); 7.78 (dd, J=7.65, 1.13 Hz,1H); 7.89 (d, J=1.26 Hz, 1H).

Following the procedure described above for Example 108 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 108a2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 401.2 (M+H⁺); UPLC rt 0.99 min.

Example 108b2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 414.2.2 (M+H⁺); UPLC rt 0.96 min.

Example 108c2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 374.2 (M+H⁺); UPLC rt 0.75 min.

Example 1092-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.112-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(520 mg, 1.47 mmol), oxazole (0.24 mL, 3.67 mmol), Pd(OAc)₂ (49 mg, 0.22mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine(141 mg, 0.29 mmol), K₂CO₃ (609 mg, 4.40 mmol) and pivalic acid (68 μL,0.59 mmol) in DMA (4 mL) was heated to 120° C. for 1 h in a microwavereactor. The mixture was then filtered and the filtrate was concentratedin vacuo. Purification of the obtained residue by flash chromatography(SiO₂, AcOEt/MeOH 99:1 to 90:10) afforded the title compound (140 mg) asa beige powder. UPLC-MS: MS 296.1 (M+H⁺); UPLC rt 0.60 min.

Step 2:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 109

A mixture of9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCl₃ (114 μL, 1.22mmol) and heated to 100° C. for 1 h. The mixture was then allowed tocool to RT, poured onto cold H₂O and extracted with DCM. The org. phaseswere dried over Na₂SO₄, filtered and concentrated in vacuo. The brownresidue obtained was taken up in DCE (5 mL) and4-cyclopropyl-1H-imidazole (79 mg, 0.73 mmol) and pyridine (148 μL, 1.83mmol) were then added. The mixture was heated to 100° C. for 1 h, andthen allowed to cool to RT, poured onto H₂O and extracted with DCM. Theorg. layers were then dried over Na₂SO₄, filtered and concentrated invacuo. Purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 9% MeOH/CO₂ for 1 min, then from 9% MeOH/CO₂ to14% MeOH/CO₂ in 6 min; then from 14% MeOH/CO₂ to 50% MeOH/CO₂ in 1 min;flow 100 mL/min; UV detection at 220 nm) afforded the title compound (7mg) as pale brown solid. UPLC-MS: MS 386.1 (M+H⁺); UPLC rt 0.79 min. ¹HNMR (400 MHz, CHLOROFORM-d): δ ppm 0.78 (m, 2H); 0.81-0.87 (m, 2H);1.79-1.93 (m, 1H); 3.14 (t, J=6.02 Hz, 2H); 3.94 (t, J=6.15 Hz, 2H);4.38 (br. s., 2H); 6.66 (s, 1H); 7.20 (s, 1H); 7.30 (s, 1H); 7.42-7.60(m, 1H); 7.77 (d, J=7.78 Hz, 1H); 7.74 (d, J=8.03 Hz, 1H); 7.90 (s, 1H);8.03 (s, 1H).

Example 1102-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

In analogy to Example 94 the title compound was synthesized from4-bromo-2-chloropyridine and tert-butyl1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. UPLC-MS: MS 415.2(M+H⁺); UPLC rt 0.77 min. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.66-0.82(m, 2H), 0.84-0.99 (m, 2H), 1.78-1.96 (m, 1H), 3.07 (t, J=6.1 Hz, 2H),3.91 (t, J=6.1 Hz, 2H), 4.41 (s, 2H), 6.79 (s, 1H), 7.11 (dd, J=8.3, 2.8Hz, 1H), 7.21 (d, J=1.0 Hz, 1H), 7.59 (d, J=5.3 Hz, 1H), 7.91 (d, J=1.3Hz, 1H), 8.07 (td, J=8.0, 2.5 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.77 (d,J=5.3 Hz, 1H).

Following the procedure described above for Example 110 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 110a9-cyclopropyl-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

UPLC-MS: MS 360.2 (M+H⁺); UPLC rt 0.85 min.

Example 110b9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

UPLC-MS: MS 361.2 (M+H⁺); UPLC rt 0.91 min.

Example 110c(R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

UPLC-MS: MS 378.2 (M+H⁺); UPLC rt 0.80 min.

Example 110d9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

UPLC-MS: MS 370.2 (M+H⁺); UPLC rt 0.86 min.

Example 1112-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.111-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(440 mg, 1.24 mmol) in dry DCE (10 mL) was treated with POCl₃ (0.23 mL,2.49 mmol) and heated to 100° C. for 1 h. The mixture was allowed tocool to RT and then poured onto H₂O and extracted with DCM. The combinedorg. layers were then dried over Na₂SO₄, filtered and concentrated invacuo. The residue obtained was taken up in DCE (10 mL) and4-ethyl-1H-imidazole (597 mg, 6.21 mmol) was added. The mixture washeated to 100° C. for 1 h. The mixture was then allowed to cool to RT,poured onto H₂O, extracted with DCM and the combined org. layers werethen dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (SiO₂, DCM to DCM/MeOH 9:1)to give the title compound (523 mg) as a brown oil. UPLC-MS: MS 433.1(M+H⁺); UPLC rt 0.93 min.

Step 2:9-(4,5-dihydrofuran-2-yl)-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.111-2

A mixture of2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(520 mg, 1.20 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane (864 mg,2.41 mmol) and Pd(PPh₃)₄ (70 mg, 0.06 mmol) in dioxane (10 mL) washeated to 150° C. for 1.5 h. The mixture was filtered and the filtrateconcentrated in vacuo. Purification by flash chromatography (SiO₂, DCMto DCM/MeOH 95:5) afforded the title compound (254 mg) as a beige solid.UPLC-MS: MS 375.3 (M+H⁺); UPLC rt 0.91 min.

Step 3:2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 111

A flask was charged with9-(4,5-dihydrofuran-2-yl)-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(250 mg, 0.67 mmol) in 20 mL THF and Raney-Nickel (100 mg, 0.67 mmol)was added. The flask was evacuated in vacuo and then filled with H₂. Themixture was stirred at RT for 36 h. The reaction mixture was thenfiltered and the filtrate concentrated in vacuo. The residue obtainedwas purified by flash chromatography (SiO₂, DCM to DCM/MeOH 9:1) and theproduct obtained was recrystallized from heptane to give the titlecompound (63 mg; racemic) as beige solid. UPLC-MS: MS 377.3 (M+H⁺); UPLCrt 0.83 min. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.13 (t, J=7.62 Hz, 3H);1.47-1.64 (m, 1H); 1.81-2.00 (m, 2H); 2.24-2.40 (m, 1H); 2.40-2.55 (m,2H); 2.74-3.04 (m, 2H); 3.59-3.74 (m, 1H); 3.81 (q, J=7.56 Hz, 1H);3.86-3.97 (m, 1H); 4.03 (q, J=7.17 Hz, 1H); 4.21 (br. s., 2H); 5.04 (t,J=7.04 Hz, 1H); 7.06-7.17 (m, 1H); 7.25-7.44 (m, 2H); 7.52 (d, J=7.43Hz, 1H); 7.89 (d, J=8.21 Hz, 1H); 8.12 (s, 1H).

Following the procedure described above for Example 111 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1122-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 405.3 (M+H⁺); UPLC rt 0.97 min.

Example 1132-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.113-1

A solution of2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(250 mg, 0.58 mmol) in dry THF was cooled to −78° C. under Ar and asolution of iPrMgCl*LiCl (1.78 mL, 2.31 mmol) was added dropwise. Themixture was stirred at −78° C. for 30 min and cyclobutanone (0.22 mL,2.90 mmol) was then added dropwise. The mixture was stirred at −78° C.for another 30 min and then at RT for 4 h. The mixture was poured onto asaturated aq. solution of NH₄Cl and the mixture was extracted withAcOEt. The combined org. phases were then dried over Na₂SO₄, filteredand concentrated in vacuo. The residue obtained was purified by flashchromatography (SiO₂, heptane to AcOEt to AcOEt/MeOH 9:1) gave the titlecompound (129 mg) as a red solid. UPLC-MS: MS 377.3 (M+H+); UPLC rt 0.76min.

Step 2:2-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 113

A solution of2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(120 mg, 0.32 mmol) in DCM was cooled to 0° C. under N₂ and treated withDAST (0.42 mL, 3.19 mmol) dropwise. The mixture was stirred for 20 minat 0° C., and the allowed to warm to RT. The reaction mixture was thenslowly poured onto a cooled saturated aq. solution of NaHCO₃ andextracted with DCM. The combined org layers were then dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product obtained waspurified by flash chromatography (SiO₂, heptane to AcOEt to AcOEt/MeOH9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton;eluent: isocratic 6% MeOH/CO₂ for 11 min; flow 100 mL/min; UV detectionat 220 nm) to afford the title compound (42 mg) as a beige solid.UPLC-MS: MS 379.2 (M+H⁺); UPLC rt 0.95 min. ¹H NMR (400 MHz, DMSO-d₆): δppm 1.10-1.19 (m, 3H); 1.46-1.64 (m, 1H); 1.88-2.09 (m, 1H); 2.47 (m,2H); 2.51-2.79 (m, 4H); 2.95 (t, J=5.28 Hz, 2H); 3.73 (t, J=6.06 Hz,2H); 4.22 (br. s., 2H); 7.07 (s, 1H); 7.33-7.48 (m, 2H); 7.58-7.67 (m,1H); 7.95 (d, J=8.21 Hz, 1H); 8.13 (s, 1H).

Following the procedure described above for Example 113 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1142-(4-ethyl-1H-imidazol-1-yl)-9-(3-fluorooxetan-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 381.2 (M+H⁺); UPLC rt 0.73 min.

Example 1152-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxyethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-acetyl-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.115-1

A mixture of9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione[example 100-1] (128 mg, 0.47 mmol) in DCE (4 mL) was treated with POCl₃(0.053 mL, 0.57 mmol) and heated to 110° C. for 1 h. The mixture wasthen allowed to cool to RT and then poured onto cooled H₂O. The mixturewas extracted with DCM and the combined org. phases were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue obtained wastaken up in DCE (4 mL) and 4-ethyl-1H-imidazole (182 mg, 1.89 mmol) wasadded. The mixture was heated to 110° C. for 1 h, then allowed to coolto rt and poured onto a saturated aq. solution of NaHCO₃. The mixturewas extracted with DCM and the combined org. layers were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(210 mg) that was used as it is in the next step. UPLC-MS: MS 349.2(M+H⁺); UPLC rt 0.71 min.

Step 2:rac-2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxyethyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 115

A solution of9-acetyl-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(210 mg, 0.36 mmol) in MeOH (20 mL) was treated with NaBH₃CN (23 mg,0.36 mmol) and the mixture was stirred at RT for 10 min. The mixture wasthen concentrated in vacuo and the residue obtained was taken up in DCMand washed with H₂O. The org layer was then dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by flash chromatography (SiO₂,heptane to AcOEt to AcOEt/MeOH 85:15) and preparative TLC (SiO₂,DCM/MeOH 95:5) afforded the title compound (6 mg). UPLC-MS: MS 351.2(M+H⁺); UPLC rt 0.65 min. ¹H NMR (400 MHz, CD₃OD): δ ppm 1.16-1.27 (m,3H); 1.44 (d, J=6.26 Hz, 3H); 2.58 (q, J=7.56 Hz, 2H); 2.97-3.17 (m,2H); 3.80 (m, 1H); 3.88-4.00 (m, 2H); 4.31-4.36 (m, 2H); 5.14 (d, J=6.65Hz, 1H); 6.95 (s, 1H); 7.34 (s, 1H); 7.37-7.49 (m, 1H); 7.67 (d, J=7.43Hz, 1H); 7.77 (d, J=7.82 Hz, 1H); 8.11 (s, 1H).

Following the procedure described above for Example 115 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1169-acetyl-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 335.2 (M+H⁺); UPLC rt 0.63 min.

Example 1179-acetyl-2-(4-cyclobutyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 375.2 (M+H⁺); UPLC rt 0.83 min.

Example 118(R)-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(prop-1-en-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.118-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(750 mg, 2.12 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (712 mg, 4.24mmol) Cs₂CO₃ (1.72 g, 5.29 mmol) and Pd(PPh₃)₄ (122 mg, 0.11 mmol) indioxane/H₂O (9:1, 20 mL) was heated to 100° C. for 2 h in a microwavereactor. The mixture was then concentrated in vacuo and the residuepurified by flash chromatography (SiO₂, heptane to AcOEt to AcOEt/MeOH85:15) to give the title compound (550 mg). UPLC-MS: MS 269.2 (M+H⁺);UPLC rt 0.83 min.

Step 2:(R)-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 118

A solution of9-(prop-1-en-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(275 mg, 1.03 mmol) in DCE (20 mL) was treated with POCl₃ (0.29 mL, 3.07mmol) and the mixture was heated to 100° C. for 1 h. The mixture wasthen allowed to cool to RT, diluted with DCM and washed with H₂O. Theorg. phase was then dried over Na₂SO₄, filtered and concentrated invacuo. The residue obtained was taken up in DCE (20 mL) and(R)-4-(1-methoxyethyl)-1H-imidazole (200 mg, 1.59 mmol) and pyridine(0.17 mL, 2.05 mmol) were then added. The mixture was heated to 110° C.for 1 h, and then allowed to cool to RT, diluted with DCM and washedwith H₂O. The org. layer was then dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO₂,heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: 4-Ethylpyridine 5μm, 250×30 mm, 60 A, Princeton; eluent: 6% MeOH/CO₂ for 1 min, then from6% MeOH/CO₂ to 11% MeOH/CO₂ in 6 min; then from 11% MeOH/CO₂ to 50%MeOH/CO₂ in 1 min; flow 100 mL/min; UV detection at 220 nm) gave thetitle compound (60 mg). UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 1.02 min. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.35 (d, J=5.87 Hz, 3H); 2.01 (s, 3H);2.90 (t, J=5.87 Hz, 2H); 3.14 (s, 3H); 3.75 (t, J=6.06 Hz, 2H);4.16-4.33 (m, 3H); 4.85 (s, 1H); 5.29 (s, 1H); 7.12 (s, 1H); 7.27-7.40(m, 2H); 7.57 (s, 1H); 7.90 (d, J=7.82 Hz, 1H); 8.18 (s, 1H).

Following the procedure described above for Example 118 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 119(S)-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 1.01 min.

Example 1209-(cyclopent-1-en-1-yl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 389.2 (M+H⁺); UPLC rt 1.05 min.

Example 1212-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(prop-1-en-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 363.0 (M+H⁺); UPLC rt 0.93 min.

Example 122(S)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 0.95 min.

Example 123(R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 0.96 min.

Starting from bromo-[O]-intermediate instead of iodo-[O]-intermediate

Example 123a9-cyclopropyl-2-(4-(oxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 386.3 (M+H⁺); UPLC rt 0.99 min.

Example 123b9-cyclopropyl-2-(4-(isoxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 386.3 (M+H⁺); UPLC rt 1.04 min.

Example 123c9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 360.3 (M+H⁺); UPLC rt 1.13 min.

Example 123d9-cyclopropyl-2-(4-methoxy-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 349.2 (M+H⁺); UPLC rt 0.99 min.

Example 123e9-cyclopropyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.UPLC-MS: MS 387.2 (M+H⁺); UPLC rt 1.16 min.

Example 123f9-cyclopropyl-2-(4-(pyridin-4-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 396.3 (M+H⁺); UPLC rt 0.87 min.

Example 1242-(4-cyclobutyl-1H-imidazol-1-yl)-9-propionyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:rac-9-(1-hydroxypropyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.124-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(2.2 g, 6.21 mmol) in dry THF (150 mL) was cooled to −78° C. under Ar,and a 2M solution of iPrMgCl in THF (18.6 mL, 37.3 mmol) was addeddropwise. The mixture was stirred at −78° C. for 30 min andpropionaldehyde (3.61 g, 62.1 mmol) was then added. The mixture wasstirred at −78° C. for another 30 min and then allowed to warm to RTovernight. The reaction mixture was poured onto a saturated aq. solutionof NH₄Cl and extracted with AcOEt. The combined org. layers were thendried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by flash chromatography (SiO₂, heptane to AcOEt/MeOH 9:1)to give the title compound (231 mg). UPLC-MS: MS 287.2 (M+H⁺); UPLC rt0.59 min.

Step 2:9-propionyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.124-2

A solution of9-(1-hydroxypropyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(231 mg, 0.78 mmol) in DCM (40 mL) was treated with Dess-Martinperiodinane (365 mg, 0.86 mmol) and the mixture was stirred at RT for 2h. The reaction mixture was then poured onto a saturated aq. solution ofNaHCO₃ and extracted with DCM. The combined org. layers were then driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by flashchromatography (SiO₂, AcOEt/MeOH 95:5) gave the title compound (225 mg).UPLC-MS: MS 285.2 (M+H⁺); UPLC rt 0.68 min.

Step 3:2-(4-cyclobutyl-1H-imidazol-1-yl)-9-propionyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 124

A solution of9-propionyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(225 mg, 0.77 mmol) in DCE (20 mL) was treated with POCl₃ (0.22 mL, 2.30mmol) and the mixture was heated to 110° C. for 1 h. The mixture wasthen allowed to cool to RT, diluted with DCM and washed with H₂O. Theorg. phase was then dried over Na₂SO₄, filtered and concentrated invacuo. The residue obtained was taken up in DCE (20 mL) and4-cyclobutyl-1H-imidazole (188 mg, 1.54 mmol) and pyridine (0.12 mL,1.54 mmol) were then added. The mixture was heated to 110° C. for 1 h,and then allowed to cool to RT, poured onto H₂O and extracted with DCM.The org. layer was then dried over Na₂SO₄, filtered and concentrated invacuo. Purification by flash chromatography (SiO₂, heptane to AcOEt toAcOEt/MeOH 85:15) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 7% MeOH/CO₂ for 1 min, then from 7% MeOH/CO₂ to12% MeOH/CO₂ in 6 min; then from 12% MeOH/CO₂ to 50% MeOH/CO₂ in 1 min;flow 100 mL/min; UV detection at 220 nm) afforded the title compound (36mg). UPLC-MS: MS 389.2 (M+H+); UPLC rt 0.95 min. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.06 (t, J=7.23 Hz, 3H); 1.55-1.90 (m, 2H); 1.99-2.27(m, 4H); 2.91-3.05 (m, 4H); 3.36 (m, 1H); 3.70 (t, J=6.06 Hz, 2H); 4.22(s, 2H); 7.10 (s, 1H); 7.41 (s, 1H); 7.49 (t, J=8.02 Hz, 1H); 7.88 (d,J=7.43 Hz, 1H); 8.05-8.20 (m, 2H).

Example 1259-(tert-butyl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(tert-butyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.125-1

A mixture of9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(2.0 g, 6.51 mmol), NiCl₂*2H₂O (0.43 g, 2.60 mmol) anddicyclohexylimidazolium tetrafluoroborate (0.83 g, 2.60 mmol) in THF (80mL) was cooled to −20° C. and then treated with a 1M solution of tBuMgCl(39.0 mL, 39.0 mmol) dropwise. The mixture was allowed to slowly warm toRT, then poured onto a saturated aq. solution of NH₄Cl and extractedwith AcOEt. The combined org. layers were then dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by flash chromatography(SiO₂, heptane to AcOEt to AcOEt/MeOH 95:5) afforded the title compound(370 mg). UPLC-MS: MS 285.2 (M+H⁺); UPLC rt 0.91 min.

Step 2:9-(tert-butyl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 125

A solution of-(tert-butyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(370 mg, 1.30 mmol) in DCE (20 mL) was treated with POCl₃ (0.24 mL, 2.60mmol) and the mixture was heated to 110° C. for 1 h. The mixture wasthen allowed to cool to RT, diluted with DCM and washed with H₂O. Theorg. phase was then dried over Na₂SO₄, filtered and concentrated invacuo. The residue obtained was taken up in DCE (20 mL) and4-(methoxymethyl)-1H-imidazole (438 mg, 3.90 mmol) was then added. Themixture was heated to 110° C. for 1 h, and then allowed to cool to RT,diluted with DCM and washed with H₂O. The org. layer was then dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by flashchromatography (SiO₂, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC(column: PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: isocratic 5%MeOH/CO₂ for 11 min; flow 100 mL/min; UV detection at 220 nm) gave thetitle compound (83 mg). UPLC-MS: MS 379.2 (M+H⁺); UPLC rt 1.04 min. ¹HNMR (400 MHz, DMSO-d6): δ ppm 1.38 (s, 9H); 3.10-3.20 (m, 2H); 3.22 (brs, 3H); 3.63 (m, 2H); 4.25 (m, 4H); 6.86 (d, J=1.96 Hz, 1H); 7.31 (s,1H); 7.49 (d, J=8.21 Hz, 1H); 7.54-7.69 (m, 2H); 8.17 (d, J=1.56 Hz,1H).

Example 1269-cyclopropyl-2-(4-((trifluoromethoxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A solution of2-(4-(((tert-butyldiphenylsilypoxy)methyl)-1H-imidazol-1-yl)-9-cyclopropyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(130 mg, 0.21 mmol, it can be obtained by analogy to example 118) in THF(15 mL) was treated with a solution of TBAF in THF (0.25 mL, 0.25 mmol)and the mixture was stirred at RT for 15 min. It was then diluted withDCM and H₂O. The aqueous phase was extracted twice with DCM and thecombined org. layers were over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by SFC (column: PPU 5 m, 250×30mm, 60 A, Princeton; eluent: 13-18% MeOH/CO2 over 11 min; flow 100mL/min; UV detection at 220 nm) and crystallization in Et₂O gave thetitle compound as a solid (28 mg). UPLC-MS: MS 349.3 (M+H⁺); UPLC rt0.82 min. ¹H NMR (400 MHz, DMSO-d6): δ ppm 0.54-0.75 (m, 2H); 0.89-1.04(m, 2H); 1.90-2.11 (m, 1H); 2.96-3.20 (m, 2H); 3.80-3.98 (m, 2H);4.29-4.46 (br s, 2H); 4.55 (s, 2H); 7.08-7.27 (m, 2H); 7.27-7.41 (m,1H); 7.79-7.90 (m, 1H); 8.05 (br s, 1H); 9.65 (br s, 1H).

Following the procedure described above for Example 126 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1279-cyclopropyl-2-(4-(1-hydroxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 375.2 (M+H⁺); UPLC rt 0.90 min.

Example 1289-cyclopropyl-2-(4-(2-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 363.2 (M+H⁺); UPLC rt 0.81 min.

Example 1299-cyclopropyl-2-(4-(1-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A solution of2-(4-acetyl-1H-imidazol-1-yl)-9-cyclopropyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(202 mg, 0.35 mmol, it can be obtained by analogy to example 118) inMeOH (8 mL) was treated with NaBH₄ (27 mg, 0.71 mmol) and the mixturewas stirred at RT for 10 min. The mixture was then diluted with DCM andH₂O, and the aqueous phase was extracte with DCM. The combined org.layers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by SFC (column: PPU 5 m, 250×30 mm, 60 A,Princeton; eluent: 12-17% MeOH/CO2 over 14 min; flow 100 mL/min; UVdetection at 220 nm) and crystallization in Et₂O gave the title compoundas a solid (41 mg). UPLC-MS: MS 363.2 (M+H⁺); UPLC rt 0.86 min. ¹H NMR(600 MHz, DMSO-d6): δ ppm 0.55-0.71 (m, 2H); 0.88-1.02 (m, 2H); 1.35 (d,J=6.40 Hz, 3H); 1.87-2.05 (m, 1H); 2.99-3.17 (m, 2H); 3.79-3.97 (m, 2H);4.17-4.31 (m, 2H); 4.55-4.71 (m, 1H); 5.01 (d, J=4.89 Hz, 1H); 7.09-7.25(m, 2H); 7.25-7.39 (m, 1H); 7.46 (s, 1H); 7.84-7.98 (m, 1H); 8.16 (br s,1H).

Example 1309-cyclopropyl-2-(4-(cyclopropyl(hydroxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A solution of1-(9-cyclopropyl-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-2-yl)-1H-imidazole-4-carbaldehyde(230 mg, 0.66 mmol, it can be obtained by analogy to example 118) in THF(35 mL) was cooled to 0° C. and then treated with a solution of cPrMgBrin THF (1.39 mL, 0.70 mmol) dropwise. The mixture was stirred at 0° C.for 1 h, and an aq. solution of saturated NH₄Cl was then added. Themixture was extracted with AcOEt, and the combined org. layers weredried over Na₂SO₄, filtered and concentrated in vacuo. Purification byflash chromatography (SiO₂, AcOEt:MeOH 100:0 to 90:10) andcrystallization in AcOEt gave the tile compound (66 mg). UPLC-MS: MS389.2 (M+H⁺); UPLC rt 0.92 min. ¹H NMR (600 MHz, DMSO-d6): δ ppm0.21-0.46 (m, 4H); 0.58-0.70 (m, 2H); 0.91-1.00 (m, 2H); 1.08-1.25 (m,1H); 1.91-2.04 (m, 1H); 3.01-3.17 (m, 2H); 3.88 (br s, 2H); 3.93-4.03(m, 1H); 4.24 (br s, 2H); 4.96 (d, J=5.27 Hz, 1H); 7.12-7.25 (m, 2H);7.25-7.35 (m, 1H); 7.49 (s, 1H); 7.91 (d, J=8.03 Hz, 1H); 8.17 (s, 1H).

Example 1319-cyclopropyl-2-(4-((trifluoromethoxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

A solution of9-cyclopropyl-2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(135 mg, 0.38 mmol) in CHCl₃ (50 mL) under Ar, was treated with3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol)and Zn(NTf₂)₂ (242 mg, 0.39 mmol). The mixture was stirred at RT for 16h, and then treated again with3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol)and Zn(NTf₂)₂ (242 mg, 0.39 mmol). After 24 h, the mixture was pouredonto H₂O and extracted with DCM. The combined org. layers were thendried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by flash chromatography (SiO₂, DCM/MeOH 100:0 to 95:5) andby SFC (column: PPU 5 m, 250×30 mm, 60 A, Princeton; eluent: isocratic20% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) togive the title compound (3 mg). UPLC-MS: MS 417.2 (M+H⁺); UPLC rt 1.15min. ¹H NMR (400 MHz, DMSO-d6): δ ppm 0.56-0.71 (m, 2H); 0.93-1.05 (m,2H); 1.91-2.04 (m, 1H); 3.14-3.20 (m, 2H); 3.89-4.01 (m, 2H); 4.34 (brs, 2H); 5.00 (s, 2H); 7.03 (s, 1H); 7.18-7.26 (m, 1H); 7.26-7.34 (m,1H); 7.69-7.85 (m, 2H); 8.25 (s, 1H).

Example 132 methyl2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate

Step 1: methyl2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate.132-1

A solution of9-bromo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(600 mg, 1.95 mmol), PdCl₂(dppf)*CH₂CL₂ (319 mg, 0.39 mmol) and Et₃N(1.4 mL, 9.77 mmol) in MeOH/Toluene (30 mL, 1:1) was flushed with CO,and then placed under CO atmosphere at RT (3.0 bar). The mixture wasthen stirred and heated to 110° C. for 2 h. The mixture was then filterover celite and the filtrate concentrated in vacuo. Purification byflash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) gave the titlecompound (255 mg). UPLC-MS: MS 287.1 (M+H⁺); UPLC rt 0.65 min.

Step 2: methyl2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate.Example 132

A solution of methyl2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate(225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93mmol) and the mixture was heated to 100° C. for 1 h. The mixture wasthen allowed to cool to RT, and then concentrated in vacuo, and driedazeotropically with toluene. The residue obtained was taken up in DCE(40 mL) and 4-cyclopropyl-1H-imidazole (261 mg, 2.41 mmol) were added.The mixture was heated to to 100° C. for 1 h and then allowed to cool toRT, diluted with DCM and washed with a saturated aq, solution of NaHCO₃.The org. layer was dried over Na₂SO₄, filtered and concentrated invacuo. Purification by flash chromatography (SiO₂, AcOEt/MeOH 100:0 to90:10) and crystallization in Et₂O/petroleum ether gave the titlecompound (116 mg). UPLC-MS: MS 377.2 (M+H⁺); UPLC rt 0.88 min. ¹H NMR(600 MHz, DMSO-d6): δ ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H);1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H);4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d,J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H).

Example 1332-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.133-3

A solution of9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(120 mg, 0.30 mmol), bis pinacol ester (153 mg, 0.60 mmol) and KOAc (89mg, 0.90 mmol) in dioxane (3 mL) was treated with PdCl₂(dppf)*CH₂Cl₂ (37mg, 0.045 mmol). The mixture was stirred under N₂ at 100° C. for 90 min,and then allowed to cool to RT. The mixture was filtered on Hyflo, andthe filtrate concentrated in vacuo. Purification by flash chromatography(SiO2, AcOEt/heptane 88:12 to 100:0) afforded the title compound (97mg). UPLC-MS: MS 446.3 (M+H⁺); UPLC rt 1.27 min.

Step 2:2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 133

A suspension of2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(95 mg, 0.21 mmol), 2-bromo-5-fluoropyridine (79 mg, 0.45 mmol) andPdCl₂(dppf)*CH₂Cl₂ (17 mg, 0.021 mmol) in DME (2.1 mL) was treated witha 2M aq. solution of Na₂CO₃ (0.5 mL, 1.06 mmol). The mixture was heatedto 80° C. for 13 h, the allowed to cool to RT and poured onto H₂O. Themixture was extracted with DCM and the combined org. layers were washedwith brine, dried over over Na₂SO₄, filtered and concentrated in vacuo.Purification by SFC (Column: Silica 5 μm, 250×30 mm, Princeton;isocratic 5% MeOH/CO₂ for 20 min; flow 100 mL/min) gave the titlecompound (19 mg). UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 1.02 min. ¹H NMR(600 MHz, DMSO-d6): δ ppm 0.71-0.90 (m, 2H); 0.90-1.00 (m, 2H);1.91-2.09 (m, 1H); 2.91-3.09 (m, 2H); 3.73 (t, J=6.24 Hz, 2H); 4.33 (s,2H); 7.06 (s, 1H); 7.40-7.56 (m, 1H); 7.66 (d, J=7.70 Hz, 1H); 7.73 (dd,J=8.71, 4.68 Hz, 1H); 7.83-8.01 (m, 2H); 8.73 (d, J=2.75 Hz, 1H); 9.03(s, 1H).

Following the procedure described above for Example 133 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 1342-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 1.05 min.

Example 1352-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.2 (M+H⁺); UPLC rt 1.00 min.

Example 1362-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 416.2 (M+H⁺); UPLC rt 0.99 min.

Example 1379-(5-fluoropyrazin-2-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 390.2 (M+H⁺); UPLC rt 0.87 min.

Example 1382-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-(2H-1,2,3-triazol-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione.136-1

A mixture of9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(600 mg, 1.69 mmol), 1H-1,2,3-triazole (421 mg, 6.10 mmol),trans-N,N-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol), cesiumcarbonate (1987 mg, 6.10 mmol) and CuI (323 mg, 1.69 mmol) in DMF (6 mL)were heated under Ar at 130° C. in the microwave for 5 hr. The mixturewas cooled to rt. Water was added and the mixture was extracted withCH₂Cl₂ (2×). The combined organic layers were dried with sodium sulfateand evaporated under reduced pressure. The crude product was purified byflash-column chromatography over silicagel (Biotage Isolera Four,eluent: DCM for 4 min, then from 0% MeOH in DCM to 5% MeOH in DCM in 26min, followed by 5% MeOH in DCM for 5 min) to yield the title compoundas yellow oil (97 mg). UPLC-MS: MS 296.2 (M+H⁺); UPLC rt 0.63 min.

Step 2:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 136

To a stirred solution of9-(2H-1,2,3-triazol-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(97 mg, 0.328 mmol) in 1,2-dichloroethane (3 mL) was added POCl₃ (0.061mL, 0.657 mmol) at rt and the resulting suspension was stirred at 100°C. for 35 min. The reaction mixture was cooled to rt and concentratedunder reduced pressure to dryness. For complete removal of POCl₃ theresidue was taken up in toluene and the solvent was evaporated underreduced pressure. The residue was dried under high vacuo at rt.

The resulting crude chloro intermediate was dissolved in1,2-dichloroethane (3 mL), 4-cyclopropyl-1H-imidazole (107 mg, 0.985mmol) was added and the mixture was stirred at 100° C. for 2 h. Thereaction mixture was allowed to warm to rt and diluted with DCM.Saturated aqueous NaHCO₃ solution was added and the mixture wasextracted twice with DCM. The combined organic layers were washed withbrine, dried with sodium sulfate, filtered and the solvent was removedunder reduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera Four, eluent: pure DCMfor 3 min, then from 0% MeOH in DCM to 5% MeOH in DCM in 14 min, 5% MeOHin DCM for 3 min) to yield a yellow foam. Further purification by SFC(column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 8%MeOH/CO₂ for 1 min, then from 8% MeOH/CO₂ to 13% MeOH/CO₂ in 6 min; flow100 mL/min; UV detection at 220 nm) gave the title compound as slightlyyellow foam (21 mg). UPLC-MS: MS 386.2 (M+H⁺); UPLC rt 0.86 min. ¹H NMR(400 MHz, DMSO-d₆) 8 ppm 0.58-0.70 (m, 2H), 0.74-0.82 (m, 2H), 1.74-1.86(m, 1H), 2.91 (t, J=5.75 Hz, 2H), 3.75 (t, J=5.87 Hz, 2H), 4.25 (s, 2H),7.22 (s, 1H), 7.43 (s, 1H), 7.54-7.63 (m, 1H), 7.76 (d, J=8.80 Hz, 1H),8.10 (s, 1H), 8.14-8.21 (m, 3H).

Example 1392-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.137-1

A solution of9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(500 mg, 1.259 mmol), bis pinacol ester (484 mg, 1.888 mmol) and KOAc(371 mg, 3.78 mmol) in dioxane (8 mL) was treated withPdCl₂(dppf)*CH₂Cl₂ (103 mg, 0.126 mmol). The mixture was stirred underN₂ at 100° C. for 90 min, and then allowed to cool to RT. The mixturewas filtered on Hyflo, and the filtrate concentrated in vacuo. The crudeproduct was purified by flash-column chromatography over silicagel(Biotage Isolera Four, eluent: 10% EtOAc in heptane for 2 min, then from10% EtOAc in heptane to 75% EtOAc in heptane in 13 min, 75% EtOAc inheptane for 3 min) to yield the title compound (232 mg). UPLC-MS: MS445.4 (M+H⁺); UPLC rt 1.18 min.

Step 2:2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 137

A suspension of2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(100 mg, 0.225 mmol), 2-bromo-5-fluoropyrazine (90 mg, 0.51 mmol) andPd(PPh₃)₄ (39 mg, 0.034 mmol) in DME (2.8 mL) was treated with a 2M aq.solution of Na₂CO₃ (0.6 mL, 1.12 mmol). The mixture was heated to 90° C.for 2 h, allowed to cool to RT and poured onto H₂O. The mixture wasextracted with DCM and the combined org. layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by flash-column chromatography over silicagel (BiotageIsolera Four, eluent: 25% EtOAc in heptane for 2 min, then from 25%EtOAc in heptane to 100% EtOAc in heptane in 10 min, 100% EtOAc inheptane for 5 min) to yield a solid which was crystallized from diethylether and afforded the title compound (57 mg). UPLC-MS: MS 415.2 (M+H⁺);UPLC rt 0.92 min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.59-0.69 (m, 2H),0.72-0.82 (m, 2H), 1.75-1.86 (m, 1H), 2.97 (t, J=5.62 Hz, 2H), 3.70 (t,J=6.11 Hz, 2H), 4.24 (br. s., 2H), 7.15 (s, 1H), 7.43 (s, 1H), 7.54 (t,J=7.82 Hz, 1H), 7.69 (d, J=7.58 Hz, 1H), 8.01-8.16 (m, 2H), 8.58 (s,1H), 8.83 (d, J=8.31 Hz, 1H).

Following the procedure described above for Example 139 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Example 140 (from Precursor Described in Preparation 17a)9-cyclopropyl-2-(4-(1-fluorocyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one

UPLC-MS: MS 433.3 (M+H⁺); UPLC rt 0.91 min.

Example 141 (from Precursor Described in Preparation 17)2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

UPLC-MS: MS 415.3 (M+H⁺); UPLC rt 0.89 min.

Example 1429-isopropoxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.142-1

A solution of9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(369 mg, 0.92 mmol), bis pinacol ester (354 mg, 1.38 mmol) and KOAc (271mg, 2.76 mmol) in dioxane (5.3 mL) was treated with PdCl₂(dppf)*CH₂Cl₂(75 mg, 0.092 mmol). The mixture was stirred under N₂ at 100° C. for 5h, and then allowed to cool to RT. The mixture was filtered on Hyflo,and the filtrate concentrated in vacuo. The crude product was purifiedby flash-column chromatography over silicagel (Biotage Isolera Four,eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 5% MeOH inDCM in 27 min, 5% MeOH in DCM for 5 min) to yield the title compound(418 mg). UPLC-MS: MS 449.3 (M+H⁺); UPLC rt 1.10 min.

Step 2:9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 142-2

2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(413 mg, 0.737 mmol) was dissolved in DME (10 mL) and hydrogen peroxide(30%, 3.40 mL, 33.3 mmol) was added at rt. The mixture was stirredovernight and the resulting crystals were filtered off (62 mg). UPLC-MS:MS 339.2 (M+H⁺); UPLC rt 0.63 min.

Step 3:9-isopropoxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 142

To a stirred suspension of9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(50 mg, 0.148 mmol) and cesium carbonate (120 mg, 0.369 mmol) in THF (1mL) and DMF (0.35 mL), isopropyl iodide (55 mg, 0.325 mmol) was added.The mixture was stirred at rt for 17 h and poured onto H₂O. The mixturewas extracted with DCM and the combined org. layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by by SFC (column: PPU 5 μm, 250×30 mm, 60 A,Princeton; eluent: 5% MeOH/CO₂ isocratic run for 20 min; flow 100mL/min; UV detection at 220 nm). The residue was crystallized fromdiethyl ether and gave the title compound as white crystals (27 mg).UPLC-MS: MS 381.2 (M+H⁺); UPLC rt 0.98 min. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.27 (d, J=6.11 Hz, 6H), 2.80 (t, J=6.11 Hz, 2H), 3.23 (s, 3H), 3.82(br. s., 2H), 4.22 (br. s., 2H), 4.27 (s, 2H), 4.64 (dt, J=12.04, 6.08Hz, 1H), 7.14 (d, J=8.07 Hz, 1H), 7.22 (s, 1H), 7.31 (t, J=8.19 Hz, 1H),7.63 (s, 1H), 7.66 (d, J=7.82 Hz, 1H), 8.20 (s, 1H).

Example 1439-cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Step 1:9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.143-1

To a stirred solution of9-bromo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione(0.464 g, 1.5 mmol) in 1,2-dichloroethane (15 mL) was added POCl₃ (0.28mL, 3.0 mmol) at RT and the resulting suspension was stirred at 100° C.for 60 min. The reaction mixture was cooled to rt and concentrated underreduced pressure to dryness. For complete removal of POCl₃ the residuewas taken up in toluene and the solvent was evaporated under reducedpressure. The residue was dried under high vacuo at RT.

The resulting crude chloro intermediate (0.491 g) was dissolved in1,2-dichloroethane (15 mL), 4-(methoxymethyl)-1H-imidazole (0.841 g, 7.5mmol) was added and the mixture was stirred at 100° C. for 1.5 h. Thereaction mixture was allowed to warm to RT and diluted with DCM. Waterand saturated aqueous NaHCO₃ solution was added and the mixture wasextracted twice with DCM. The combined organic layers were washed withbrine, dried with sodium sulfate, filtered and the solvent was removedunder reduced pressure. The crude product was purified by flash-columnchromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH inDCM for 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 25 min, 4%MeOH in DCM for 5 min) to yield a yellow foam (149 mg). UPLC-MS: MS403.1/405.1 (M+H⁺); UPLC rt 0.82 min.

Step 2:9-cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.Example 143

9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one(148 mg, 0.367 mmol) was dissolved in toluene (3.6 mL) and S-Phos (49mg, 0.117 mmol), cyclopropylboronic acid (66 mg, 0.734 mmol) and K₃PO₄(164 mg, 0.771 mmol) were added. The suspension was degassed, Pd(OAc)₂(17 mg, 0.073 mmol) was added under Argon and the mixture was heated at100° C. for 1.5 h. The mixture was allowed to warm to RT and filteredthrough a pad of celite and the solvent was removed under reducedpressure. The crude product was purified by flash-column chromatographyover silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min,then from 1% MeOH in DCM to 4% MeOH in DCM in 12 min, 4% MeOH in DCM for3 min) to yield a yellow foam. Further purification by SFC (column:2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 11% MeOH/CO₂for 1 min, then from 11% MeOH/CO₂ to 16% MeOH/CO₂ in 6 min; flow 100mL/min; UV detection at 220 nm) gave the title compound as white foam(30 mg). UPLC-MS: MS 365.3 (M+H⁺); UPLC rt 0.85 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.51-0.66 (m, 2H), 0.86-0.98 (m, 2H), 1.86-2.00 (m, 1H),2.97-3.09 (m, 2H), 3.21 (s, 3H), 3.54-3.66 (m, 1H), 3.67-3.77 (m, 1H),4.11-4.30 (m, 3H), 5.26 (d, J=15.31 Hz, 1H), 5.73 (dd, J=9.91, 4.89 Hz,1H), 6.95 (d, J=7.28 Hz, 1H), 7.12-7.21 (m, 1H), 7.21-7.27 (m, 1H), 7.57(s, 1H), 8.10 (s, 1H).

Biological Testing 1.1 In-Vitro Testing

Activity of compounds of the present invention was examined bydetermination to what extent the glutamate-induced elevation of theintracellular calcium concentration in L(tk-) cells expressing humanmGluR5a receptors (see L. P. Daggett et al., Neuropharm. Vol. 34, pages871-886, 1995) is inhibited by utilizing methods as described e.g. by L.P. Daggett et al., Neuropharm. Vol. 34, pages 871-886 (1995) and P. J.Flor et al., J. Neurochem. Vol. 67, pages 58-63 (1996).

Activity of compounds of the present invention with respect to mGluR1antagonism was examined by an assay based on measurements of L-glutamateinduced intracellular calcium increases using a 96 well plate-basedFluorometric Imaging Plate Reader (FLIPR), and CHO cells stablyexpressing human mGluR1. L-glutamate induced robust calcium responsesvia human mGluR1 in a concentration-dependent manner and in the lowmicromolar range. The table below represents IC₅₀ values of theinhibition of the glutamate-induced elevation of the intracellularcalcium concentration.

mGluR5 mGluR1 IC₅₀ IC₅₀ Example (μM) (μM)  1 0.327 6.4  2 0.09 0.027  30.22 0.585  4 0.18 0.15  5 0.044 0.015  6 0.075 3.05  7 0.024 0.21  80.022 4.9  9 0.6 >10 10 0.345 0.94 11 0.17 0.69 12 0.046 1.3 13 0.0820.53 14 0.55 >10 15 42% ^(a) 44% ^(a) 16 2.2 3.5 17 2.2 >10 18 4.1 >1019 4.5 0.8 20 1.2 2.8 21 3.9 5.2 22 0.071 >10 23 0.022 >10 24 0.035 >1025 0.066 >10 26 0.235 >10 27 0.437 >10 28 0.08 4.8 29 0.09 0.008 30 0.151.4 31 0.167 1.3 32 0.01 0.035 33 0.013 1.4 34 0.041 0.093 35 0.0140.015 36 3.8 6.9  36a 5.5  1% ^(a) 37 0.077 2.2 38 0.05 0.022 39 0.611.6 40 5.2 >10 41 0.032 >10 42 0.032 3.4 43 0.685 >10 44 1.6 >10 450.7 >10 46 0.27 2.2 47 0.071 3.4 48 0.035 2.3 49 1.3 >10 50 0.046 >10 510.035 >10 52 0.066 >10 53 0.007 >10 54 0.011 >10 55 4.9 >10 56 24% ^(a) 0% ^(a) 57 0.014 4.5 58 26% ^(a) 8.9 59 23% ^(a) 6.5 60 27% ^(a) 15%^(a) 61 0.345 3.1 62 0.595 1.6 63 0.535 3.2 64 4.3 >10 65 0.21 1.5 660.78 >10 67 0.715 1.4 68 1.7 >10 69 0.02 >10 70 0.049 >10 71 0.027 6.472 0.275 >10 73 3.5 >10 74 0.022 1.2 75 0.009 0.17 76 0.034 4.2 77 0.03273% ^(a) 78 0.54 >10 79 0.13 >10 80 0.145 >10 81 0.036 >10 82 0.072 >1083 0.205 >10 84 0.028 >10 85 0.039 1.6 86 0.012 5.9 87 0.148 56% ^(a) 880.131 47% ^(a)  88a 0.005 24% ^(a)  88b 0.020 >2  88c 0.271 >10  88d0.031 >2  88e 0.034 3.881  88f 0.100 1.953  88g 0.017 0.761  88h 0.0461.053  88i 0.340 >10  88j 0.056 1.857  88k 0.069 5.86 89 0.028 0.65 900.01 1.5 91 0.009 0.22 92 <0.001 0.636 93 0.003 1.5 94 2.7 >10   95-10.02 10   95-2 0.011 >10   96-1 0.006 0.54   96-2 0.002 0.289 97 0.0375.9 98 0.014 2.4 99 0.083 >2  99a 0.077 >10  99b 41% ^(b) >10  99c 31%^(b) >10  99d 0.347 >2  99e 0.127 8.261  99f 0.102 11.993  99g 0.22018.193  99h 0.038 not tested  99i 0.016 0.687  99j 0.007 3.206  99k0.003 0.561  99l 0.002 0.702  99m 0.002 0.672  99n 0.006 2.079  99o0.050 >10  99p 0.002 0.814  99q 0.088 >6  99r 0.136 >10  99s 0.153 >10100  0.019 0.56 101  0.026 >10 102  0.016 >10 103  0.018 >10 104  0.0071.3 105  0.122 >10 106  0.182 >10 106a 0.068 >10 106b 0.168 7.333 106c1.090 >10 107  0.835 >10 108  0.018 3.3 108a 0.091 >10 108b 0.023 1.919108c 0.115 >10 109  0.01 1.8 110  0.27 >10 110a 0.328 >2 110b 0.758 >10110c 72% ^(b) >10 110d 57% ^(b) >10 111  0.053 9.3 112  0.515 >10 113 0.12 2.3 114  1.6 >10 115  0.495 >10 116  0.41 >10 117  0.035 0.66 118 0.018 >10 119  0.024 2.6 120  0.007 0.89 121  0.014 0.49 122  0.005 1.1123  0.003 7 123a 0.012 >2 123b 0.001 2.342 123c 0.008 0.226 123d 0.0110.511 123e 0.056 1.644 123f 0.108 >2 124  0.005 3.3 125  0.18 >2 126 0.006 0.712 127  0.007 1.195 128  0.001 0.041 129  0.002 1.5 130  0.0273.312 131  0.046 >2 132  0.061 2.068 133  0.215 >10 134  0.198 >10 135 0.829 >10 136  0.019 >2 137  0.048 >10 138  0.079 1.485 139  0.017 1.103140  0.093 >10 141  0.026 0.402 142  0.273 >2 143  0.282 >10 ^(a) %inhibition at 10 μM; ^(b) % inhibition at 2 μM

The following two compounds of formula (I) were tested at 10 μM in theabove described mGluR5a antagonism test and less than 20% inhibition wasseen:

-   9-chloro-2-(5-methyl-1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;    and-   2-(4-ethyl-1H-imidazol-1-yl)-9-(3-hydroxyoxetan-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one.

1-15. (canceled)
 16. A method for the treatment of a substance-relateddisorder comprising administration of a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof to a patient in need of treatment thereof

wherein A is a fused five- to seven-membered monocyclic ring systemwhich may be aromatic, saturated or unsaturated non-aromatic and whichmay contain from 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur; R₁ is —X₂—B₂; X₂ is bond or C₁₋₃alkylene, wherein one carbonatom of the C₁₋₃alkylene may be replaced by a group selected fromcarbonyl; oxygen; sulfur; —S(O)—; —S(O)₂—; amino, which may besubstituted by C₁₋₄alkyl; —NH—C(O)—; —C(O)—NH—; —C(O)—O—; —O—C(O)—;—NH—S(O)₂—; —S(O)₂—NH—; and —NHC(O)NH—; B₂ is a three- to seven-memberedmonocyclic ring system which may be aromatic, saturated or unsaturatednon-aromatic and which may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₆; each R₆ independently ishalogen, hydroxy, cyano, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₆ at the same ring atom together are oxo; mis 0, 1, 2, 3 or 4; each R₂ independently is halogen, cyano, hydroxy,amino, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen; n is 0, 1, 2, 3 or 4; each R₃ independentlyis halogen, cyano, hydroxy, amino, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen; R₄ is hydrogen, halogen, cyano, hydroxy,amino, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl;C₁₋₄alkylamino-C₁₋₄alkyl; di-(C₁₋₄alkyl)amino-C₁₋₄alkyl;C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl; C₂₋₄halogenalkenyl; C₂₋₄alkinyl;C₂₋₄halogenalkinyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₇₋₄alkyl)amino or C₃₋₆cycloalkyl, wherein one carbon atom of theC₃₋₆cycloalkyl may be replaced by an oxygen atom and wherein theC₃₋₆cycloalkyl may be attached directly to the ring system or via aC₁₋₂alkylene or an oxygen; B₁ is a five- to six-membered aromatic ringsystem, which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₇; each R₇ independently ishalogen, cyano, hydroxy, amino, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄hydroxyalkyl; C₁₋₄aminoalkyl; C₁₋₄alkylamino-C₁₋₄alkyl;di-(C₁₋₄alkyl)amino-C₁₋₄alkyl; C₁₋₄alkoxy-C₁₋₄alkyl; C₂₋₄alkenyl;C₂₋₄halogenalkenyl; C₂₋₄alkinyl; C₂₋₄halogenalkinyl; C₁₋₄alkoxy;C₁₋₄alkoxy-C₁₋₄alkoxy C₁₋₄halogenalkoxy; C₁₋₄alkyl-amino;di-(C₁₋₄alkyl)amino; C₁₋₄alkoxycarbonyl; or a three- to seven-memberedmonocyclic ring system which may be aromatic, saturated or unsaturatednon-aromatic and which may contain from 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₈; each R₈ independently ishalogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₈ at the same ring atom together are oxo; ortwo R₇ at adjacent ring atoms atoms form together with said ring atoms afused five- to seven-membered monocyclic unsaturated non-aromatic ringsystem which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may in turn besubstituted once or more than once by R₉; each R₉ independently ishalogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl, C₁₋₄alkoxy, orC₁₋₄halogenalkoxy; or two R₉ at the same ring atom together are oxo. 17.The method according to claim 1, wherein A is phenyl.
 18. The methodaccording to claim 1, wherein R₁ is —X₂—B₂, wherein X₂ is bond; B₂ isC₃₋₆cycloalkyl which may be substituted once or more than once by R₆; orB₂ is a five- to six-membered aromatic ring system which may containfrom 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur,wherein the ring system may in turn be substituted once or more thanonce by R₆; each R₆ independently is halogen, hydroxy, cyano, C₁₋₄alkyl,C₁₋₄halogenalkyl, C₁₋₄alkoxy, or C₁₋₄halogenalkoxy.
 19. The methodaccording to claim 1, wherein m is 0, 1 or 2; each R₂ independently ishalogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy orC₃₋₆cycloalkyl; n is 0; and R₄ is hydrogen.
 20. The method according toclaim 1, wherein B₁ is a five- to six-membered aromatic ring system,which contains from 1 to 4 hetero atoms selected from nitrogen, oxygenand sulfur, wherein the ring system may in turn be substituted once ormore than once by R₇; and wherein each R₇ independently is halogen,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₇₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy orC₃₋₆cycloalkyl.
 21. The method according to claim 1, wherein A isphenyl; R₁ is —X₂—B₂, wherein X₂ is bond; B₂ is C₃₋₆cycloalkyl which maybe substituted once or more than once by R₆; or B₂ is a five- tosix-membered aromatic ring system which may contain from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring systemmay in turn be substituted once or more than once by R₆; each R₆independently is halogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄halogenalkyl,C₁₋₄alkoxy, or C₁₋₄halogenalkoxy; m is 0, 1 or 2; each R₂ independentlyis halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxyor C₃₋₆cycloalkyl; n is 0, 1 or 2; each R₃ independently is halogen,C₁₋₄alkyl; C₁₋₄halogenalkyl; C₁₋₄alkoxy; C₁₋₄halogenalkoxy orC₃₋₆cycloalkyl; R₄ is hydrogen, halogen, C₁₋₄alkyl; C₁₋₄ halogenalkyl;C₁₋₄alkoxy; C₁₋₄halogenalkoxy or C₃₋₆cycloalkyl; B₁ is a five- tosix-membered aromatic ring system, which contains from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring systemmay in turn be substituted once or more than once by R₇; and whereineach R₇ independently is halogen, C₁₋₄alkyl; C₁₋₄halogenalkyl;C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy or C₃₋₆cycloalkyl.
 22. The methodaccording to claim 1, wherein said compound of formula (I) is selectedfrom the group consisting of2-(2-methoxypyridin-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(5-methylfuran-2-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(1-methyl-1H-pyrazol-3-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(1-methyl-1H-pyrazol-4-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(furan-2-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-methoxyphenyl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(1-isopropyl-1H-pyrazol-4-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-methoxyphenyl)-9-phenyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(2-methoxypyridin-4-yl)-9-(pyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(furan-3-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(2-methoxypyridin-4-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(41-1)-one;9-(6-fluoropyridin-3-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(3-fluoropyridin-4-yl)-2-(2-methoxypyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(1-methyl-1H-imidazol-4-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(1-methyl-1H-pyrazol-3-yl)-9-(2-methylpyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one,(R)-2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(S)-2-(3-methoxyphenyl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(1H-pyrazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclobutyl-1H-imidazol-1-yl)-9-morpholino-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-isopropyl-1H-imidazol-1-yl)-9-(1-methyl-1H-imidazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-O-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-yl)-9-(furan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(5-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(pyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(pyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(6-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-chloro-1H-imidazol-1-yl)-9-(5-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(6-fluoropyridin-3-yl)-2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-yl)-9-(4-fluorophenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-methyloxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclobutyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclobutyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;4-(6-fluoropyridin-3-yl)-11-(4-isopropyl-1H-imidazol-1-yl)-5,6-dihydro-[1,4]diazepino[1,7-h][1,7]naphthyridin-8(9H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2,6-difluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-ethyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-methylisothiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-O-9-(oxazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethynyl-1H-imidazol-1-yl)-9-(thiazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(2-fluoropyridin-3-yl)-2-(4-(oxazol-2-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(R)-2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(S)-2-(4-ethyl-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(R)-2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(S)-2-(4-(tert-butyl)-1H-imidazol-1-yl)-9-(tetrahydrofuran-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-ethyl-1H-imidazol-1-yl)-9-(3-fluorooxetan-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(cyclopent-1-en-1-yl)-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(S)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(3-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(thiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methylthiazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(2-methoxyethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(4-methylthiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-(ethoxymethyl)-1H-imidazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(4-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(3-(trifluoromethyl)-1H-pyrazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-hydroxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-methoxypyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyrimidin-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-fluoropyridin-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclobutyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-12-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;(R)-9-cyclopropyl-12-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-11-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(fluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;10-fluoro-9-(6-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-10-fluoro-9-(2-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;10-fluoro-9-(2-fluoropyridin-3-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;10-fluoro-9-(2-fluoropyridin-3-yl)-2-(4-methyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(6-fluoropyridin-3-yl)-2-(4-(1-methoxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(pyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-(6-fluoropyridin-3-yl)-2-(4-(3-hydroxyoxetan-3-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclobutyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-methyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;(R)-9-cyclopropyl-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;9-cyclopropyl-2-(4-(difluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a][2,6]naphthyridin-5(4H)-one;9-cyclopropyl-2-(4-(oxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(isoxazol-5-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-methoxy-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(pyridin-4-yl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(1-hydroxycyclopropyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(2-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(1-hydroxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-(cyclopropyl(hydroxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-cyclopropyl-2-(4-((trifluoromethoxy)methyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(4-fluoropyridin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2H-1,2,3-triazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(5-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;2-(4-cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyrazin-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;9-isopropoxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one;or a pharmaceutically acceptable salt thereof.
 23. The method accordingto claim 1 wherein the compound of formula (I) is2-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula:

or a pharmaceutically acceptable salt thereof.
 24. The method accordingto claim 1 wherein the compound of formula (I) is9-Cyclopropyl-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 25. The method accordingto claim 1 wherein the compound of formula (I) is2-(4-Cyclopropyl-1H-imidazol-1-yl)-9-(6-fluoropyridin-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 26. The method accordingto claim 1 wherein the compound of formula (I) is9-Cyclopropyl-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 27. The method accordingto claim 1 wherein the compound of formula (I) is2-(4-Cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 28. The method accordingto claim 1 wherein the compound of formula (I) is2-(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)-9-(thiazol-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 29. The method accordingto claim 1 wherein the compound of formula (I) is9-(5-fluoropyrazin-2-yl)-2-(3-methyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 30. The method accordingto claim 1 wherein the compound of formula (I) is(R)-9-cyclopropyl-10-fluoro-2-(4-(1-methoxyethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 31. The method accordingto claim 1 wherein the compound of formula (I) is9-Cyclopropyl-10-fluoro-2-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-onehaving the following formula

or a pharmaceutically acceptable salt thereof.
 32. The method accordingto claim 1 wherein the substance-related disorder is substance abuse.33. The method according to claim 1 wherein the substance-relateddisorder is substance dependence.
 34. The method according to claim 1wherein the substance-related disorder is substance withdrawal.